Acetamide thienotriazolodiazepines and uses thereof

ABSTRACT

The present invention provides compounds of Formula (I), and pharmaceutically compositions thereof. Compounds of Formula (I) are binders of bromodomains and/or bromodomain-containing proteins (e.g., bromo and extra terminal (BET) proteins). Also provided are methods, uses, and kits using the compounds and pharmaceutical compositions for inhibiting the activity (e.g., increased activity) of bromodomains and/or bromodomain-containing proteins and for treating and/or preventing in a subject diseases associated with bromodomains or bromodomain-containing proteins (e.g., proliferative diseases, cardiovascular diseases, viral infections, fibrotic diseases, metabolic diseases, endocrine diseases, and radiation poisoning). The compounds, pharmaceutical compositions, and kits are also useful for male contraception.

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S.Provisional Application, U.S. Ser. No. 62/217,544, filed Sep. 11, 2015,which is incorporated herein by reference.

BACKGROUND

Bromodomain-containing proteins are of substantial biological interest,as components of transcription factor complexes and determinants ofepigenetic memory. For example, the bromo and extra terminal (BET)protein family (e.g., bromodomain-containing protein 2 (BRD2),bromodomain-containing protein 3 (BRD3), bromodomain-containing protein4 (BRD4), and bromodomain testis-specific protein (BRDT)) shares acommon domain architecture featuring two amino-terminal bromodomainsthat exhibit high levels of sequence conservation, and a more divergentcarboxy-terminal recruitment domain (Filippakopoulos et al., Nature2010, 468, 1067-1073). BRD2 and BRD3 are reported to associate withhistones along actively transcribed genes and may be involved infacilitating transcriptional elongation (Leroy et al., Mol. Cell. 2008,30, 51-60). It has also been reported that BRD4 or BRD3 may fuse withnuclear protein in testis (NUT), forming novel fusion oncogenes BRD4-NUTor BRD3-NUT, in a highly malignant form of epithelial neoplasia (Frenchet al., Cancer Res., 2003, 63, 304-307; French et al., J. Clin. Oncol.2004, 22, 4135-4139). Data suggests that BRD-NUT fusion proteinscontribute to carcinogenesis (French et al., Oncogene 2008, 27,2237-2242). BRDT is uniquely expressed in the testes and ovary. Allfamily members of BET have been reported to have some function incontrolling or executing aspects of the cell cycle and have been shownto remain in complex with chromosomes during cell division, suggesting arole in the maintenance of epigenetic memory. In addition, some virusesmake use of BET proteins to tether their genomes to the host cellchromatin, as part of the process of viral replication (You et al., Cell2004, 117, 349-360). BRD4 appears to be involved in the recruitment ofthe pTEF-b complex to inducible genes, resulting in phosphorylation ofRNA polymerase and increased transcriptional output (Hargreaves et al.,Cell 2009, 138, 129-145). In humans, BRD2, BRD3, BRD4, and BRDT exhibitsimilar gene arrangements, domain organizations, and some functionalproperties (Wu et al., J. Biol. Chem. 2007, 282, 13141-13145).

SUMMARY OF THE INVENTION

Recently, compounds have been reported to be bromodomain binding agents,e.g., international PCT publications WO 2012/075383, WO 2011/054553, WO2011/054841, WO 2011/054844, WO 2011/054845, WO 2011/054846, WO2011/054848, WO 2011/143669, and WO 2011/161031. Moreover, Japanesepatent application publication JP 2008/156311 discloses a benzimidazolederivative that is a BRD2 bromodomain binding agent and has been founduseful in treating viral infections and inhibiting viral replication.International PCT publication WO 2009/084693 discloses a series ofthienotriazolodiazepine derivatives that inhibit the binding between anacetylated histone and a bromodomain-containing protein which are usefulas anti-cancer agents. International PCT publication WO 2011/054843suggests compounds which inhibit the binding of a bromodomain with itscognate acetylated proteins may be useful in the treatment of autoimmuneand inflammatory diseases. However, there remains a need for additionalpotent and safe bromodomain binders.

The present invention provides compounds of Formula (I). In certainembodiments, compounds of Formula (I) are thienotriazolodiazepinescomprising an acetamide group. The compounds described herein may to bebinders of transcription factors, such as bromodomain-containingproteins (e.g., BET proteins) and may be useful in male contraceptionand in treating and/or preventing a wide range of diseases (e.g.,diseases associated with bromodomains, diseases associated with theactivity (e.g., aberrant activity) of bromodomains, diseases associatedwith bromodomain-containing proteins, and disease associated with theactivity (e.g., aberrant activity) of bromodomain-containing proteins).Diseases that may be treated and/or prevented by the methods of thedisclosure include, but are not limited to, proliferative diseases(e.g., cancers, benign neoplasms, pathological angiogenesis,inflammatory diseases, and autoimmune diseases), cardiovasculardiseases, viral infections, fibrotic diseases, neurological diseases,metabolic diseases, endocrine diseases, and radiation poisoning. Alsoprovided in the present disclosure are pharmaceutical compositions,kits, methods, and uses including or using a compound described herein.

In one aspect, the present invention provides compounds of Formula (I):

and pharmaceutically acceptable salts, solvates, hydrates, polymorphs,co-crystals, tautomers, stereoisomers, isotopically labeled derivatives,and prodrugs thereof.

In still another aspect, the present disclosure provides pharmaceuticalcompositions including a compound described herein (e.g., a compound ofFormula (I)), and optionally a pharmaceutically acceptable excipient. Incertain embodiments, the pharmaceutical compositions described hereininclude a therapeutically or prophylactically effective amount of acompound described herein. The pharmaceutical composition may be usefulfor treating and/or preventing a disease in a subject in need thereof.The pharmaceutical composition may also be useful in inhibiting thereplication of a virus, in killing a virus, in inhibiting the activityof a bromodomain-containing protein, in inhibiting the activity of abromodomain, in inhibiting the binding of a bromodomain of abromodomain-containing protein to an acetylated lysine residue of ahistone or other protein, in modulating (e.g., inhibiting)transcriptional elongation, in modulating (e.g., down-regulating orinhibiting) the expression (e.g., transcription) of a gene that isregulated by a bromodomain-containing protein, in inducing apoptosis,and/or inducing G1 arrest, in a subject or cell.

In certain embodiments, the disease described herein is associated withthe activity (e.g., aberrant activity, increased activity) of abromodomain-containing protein. In certain embodiments, the disease isassociated with the function (e.g., dysfunction) of abromodomain-containing protein. In certain embodiments, the disease isassociated with the activity (e.g., aberrant activity, increasedactivity) of a bromodomain. In certain embodiments, the disease isassociated with the function (e.g., dysfunction) of a bromodomain.

In certain embodiments, the disease is a proliferative disease (e.g.,cancer, benign neoplasm, pathological angiogenesis, an inflammatorydisease, or an autoimmune disease), cardiovascular disease, viralinfection, fibrotic disease, neurological disease, metabolic disease,endocrine disease, or radiation poisoning.

Another aspect of the present disclosure relates to methods of treatinga disease in a subject in need thereof.

In another aspect, the present disclosure provides methods of preventinga disease in a subject in need thereof.

Another aspect of the present disclosure relates to methods of reducingthe risk of developing a disease in a subject in need thereof.

Another aspect of the present disclosure relates to methods ofinhibiting the replication of a virus (e.g., human immunodeficiencyvirus (HIV), human papillomavirus (HPV), hepatitis C virus (HCV), herpessimplex virus (HSV), Ebola virus, and influenza virus).

Another aspect of the present disclosure relates to methods of killing avirus (e.g., human immunodeficiency virus (HIV), human papillomavirus(HPV), hepatitis C virus (HCV), herpes simplex virus (HSV), Ebola virus,and influenza virus).

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain-containing protein in a subject or cell.In certain embodiments, the activity of a bromodomain-containing proteinis aberrant or unwanted activity (e.g., an increased activity) of thebromodomain-containing protein. In certain embodiments, the activity ofthe bromodomain-containing protein is selectively inhibited (e.g., whencompared to the activity of a kinase that is different from thebromodomain-containing protein) by the methods.

In yet another aspect, the present disclosure provides methods ofinhibiting the activity of a bromodomain in a subject or a biologicalsample. In certain embodiments, the activity of a bromodomain beinginhibited is aberrant or unwanted activity (e.g., an increased activity)of the bromodomain.

In yet another aspect, the present disclosure provides methods ofinhibiting the binding of a bromodomain to an acetylated lysine residueof a second protein (e.g., histone) in a subject or biological sample.In certain embodiments, the second protein is a protein that includes atleast one acetylated lysine residue.

In still another aspect, the present disclosure provides methods ofmodulating the expression (e.g., transcription) of a gene that isregulated by a bromodomain-containing protein in a subject or biologicalsample. In certain embodiments, the methods of modulating the expression(e.g., transcription) of a gene are methods of down-regulating orinhibiting the expression (e.g., transcription) of the gene. The methodmay result in decreased levels of a gene product (e.g., RNA, protein) ina cell.

In still another aspect, the present disclosure provides methods ofmodulating (e.g., inhibiting) transcriptional elongation in a cell of asubject or biological sample.

Another aspect of the disclosure relates to methods of inducingapoptosis (e.g., apoptosis of a cancer cell) in a cell of a subject orbiological sample.

Another aspect of the disclosure relates to methods of method forinducing G1 arrest in a cell of a subject or biological sample.

The methods of the present disclosure include administering to thesubject an effective amount of a compound or pharmaceutical compositiondescribed herein. The methods of the present disclosure includecontacting a biological sample (e.g., a cell) with an effective amountof a compound or pharmaceutical composition described herein. Themethods of the present disclosure include contacting a virus with aneffective amount of a compound or pharmaceutical composition describedherein. In certain embodiments, the effective amount is atherapeutically effective amount. In certain embodiments, the effectiveamount is a prophylactically effective amount. In certain embodiments,the methods of the present disclosure further include administering tothe subject an additional pharmaceutical agent in combination with acompound or pharmaceutical composition described herein. In certainembodiments, the methods of the present disclosure further includecontacting a biological sample (e.g., a cell) with an additionalpharmaceutical agent in combination with a compound or pharmaceuticalcomposition described herein. In certain embodiments, the methods of thepresent disclosure further include contacting a virus with an additionalpharmaceutical agent in combination with a compound or pharmaceuticalcomposition described herein. In certain embodiments, the combination ofthe pharmaceutical agent and the compound or pharmaceutical compositiondescribed herein is synergistic.

Another aspect of the disclosure relates to methods of screening alibrary of compounds to identify a compound that is useful in a methodof the disclosure.

Another aspect of the present disclosure relates to kits comprising acontainer with a compound or pharmaceutical composition describedherein. The kits described herein may include a single dose or multipledoses of the compound or pharmaceutical composition described herein.The provided kits may be useful in a method of the disclosure. Incertain embodiments, the kit further includes instructions for using thekit.

In yet another aspect, the present disclosure provides compounds andpharmaceutical compositions described herein for use in a method of thedisclosure.

The present application refers to various issued patents, publishedpatent applications, journal articles, and other publications, all ofwhich are incorporated herein by reference. The details of one or moreembodiments of the disclosure are set forth herein. Other features,objects, and advantages of the disclosure will be apparent from theDetailed Description, the Figures, the Examples, and the Claims.

Definitions Chemical terms

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in OrganicChemistry, Thomas Sorrell, University Science Books, Sausalito, 1999;Smith and March March's Advanced Organic Chemistry, 5^(th) Edition, JohnWiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various stereoisomeric forms, e.g., enantiomersand/or diastereomers. For example, the compounds described herein can bein the form of an individual enantiomer, diastereomer or geometricisomer, or can be in the form of a mixture of stereoisomers, includingracemic mixtures and mixtures enriched in one or more stereoisomer.Isomers can be isolated from mixtures by methods known to those skilledin the art, including chiral high pressure liquid chromatography (HPLC)and the formation and crystallization of chiral salts; or preferredisomers can be prepared by asymmetric syntheses. See, for example,Jacques et al., Enantiomers, Racemates and Resolutions (WileyInterscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977);Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); and Wilen, S. H. Tables of Resolving Agents and OpticalResolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind. 1972). The disclosure additionally encompasses compounds asindividual isomers substantially free of other isomers, andalternatively, as mixtures of various isomers.

In a formula,

is a single bond where the stereochemistry of the moieties immediatelyattached thereto is not specified, - - - is absent or a single bond, and

or

is a single or double bond.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds that differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of hydrogen by deuterium ortritium, replacement of ¹⁹F with ¹⁸F, or the replacement of ¹²C with ¹³Cor ¹⁴C are within the scope of the disclosure. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclicgroups. Likewise, the term “heteroaliphatic” refers to heteroalkyl,heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term “alkyl” refers to a radical of a straight-chain or branchedsaturated hydrocarbon group having from 1 to 10 carbon atoms (“C₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). In someembodiments, an alkyl group has 2 to 6 carbon atoms (“C₂₋₆ alkyl”).Examples of C₁₋₆ alkyl groups include methyl (C₁), ethyl (C₂), propyl(C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl,sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl,neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C₆) (e.g.,n-hexyl). Additional examples of alkyl groups include n-heptyl (C₇),n-octyl (C₈), and the like. Unless otherwise specified, each instance ofan alkyl group is independently unsubstituted (an “unsubstituted alkyl”)or substituted (a “substituted alkyl”) with one or more substituents(e.g., halogen, such as F). In certain embodiments, the alkyl group isan unsubstituted C₁₋₁₀ alkyl (such as unsubstituted C₁₋₆ alkyl, e.g.,—CH₃ (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g.,unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)),unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu),unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl(sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, thealkyl group is a substituted C₁₋₁₀ alkyl (such as substituted C₁₋₆alkyl, e.g., —CF₃, Bn).

The term “haloalkyl” is a substituted alkyl group, wherein one or moreof the hydrogen atoms are independently replaced by a halogen, e.g.,fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkylmoiety has 1 to 8 carbon atoms (“C₁₋₈ haloalkyl”). In some embodiments,the haloalkyl moiety has 1 to 6 carbon atoms (“C₁₋₆ haloalkyl”). In someembodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C₁₋₄haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbonatoms (“C₁₋₃ haloalkyl”). In some embodiments, the haloalkyl moiety has1 to 2 carbon atoms (“C₁₋₂ haloalkyl”). Examples of haloalkyl groupsinclude —CHF₂, —CH₂F, —CF₃, —CH₂CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂,—CF₂Cl, and the like.

The term “heteroalkyl” refers to an alkyl group, which further includesat least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected fromoxygen, nitrogen, or sulfur within (i.e., inserted between adjacentcarbon atoms of) and/or placed at one or more terminal position(s) ofthe parent chain. In certain embodiments, a heteroalkyl group refers toa saturated group having from 1 to 10 carbon atoms and 1 or moreheteroatoms within the parent chain (“heteroC₁₋₁₀ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 9carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₉ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 8 carbon atoms and 1 or more heteroatomswithin the parent chain (“heteroC₁₋₈ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1or more heteroatoms within the parent chain (“heteroC₁₋₇ alkyl”). Insome embodiments, a heteroalkyl group is a saturated group having 1 to 6carbon atoms and 1 or more heteroatoms within the parent chain(“heteroC₁₋₆ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms withinthe parent chain (“heteroC₁₋₅ alkyl”). In some embodiments, aheteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC₁₋₄ alkyl”). In someembodiments, a heteroalkyl group is a saturated group having 1 to 3carbon atoms and 1 heteroatom within the parent chain (“heteroC₁₋₃alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 1 to 2 carbon atoms and 1 heteroatom within the parent chain(“heteroC₁₋₂ alkyl”). In some embodiments, a heteroalkyl group is asaturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In some embodiments, a heteroalkyl group is a saturated grouphaving 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parentchain (“heteroC₂₋₆ alkyl”). Unless otherwise specified, each instance ofa heteroalkyl group is independently unsubstituted (an “unsubstitutedheteroalkyl”) or substituted (a “substituted heteroalkyl”) with one ormore substituents. In certain embodiments, the heteroalkyl group is anunsubstituted heteroC₁₋₁₀ alkyl. In certain embodiments, the heteroalkylgroup is a substituted heteroC₁₋₁₀ alkyl.

The term “alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In someembodiments, an alkenyl group has 2 to 9 carbon atoms (“C₂₋₉ alkenyl”).In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C₂₋₈alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms(“C₂₋₇ alkenyl”). In some embodiments, an alkenyl group has 2 to 6carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, an alkenyl group has2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In some embodiments, an alkenylgroup has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”). In some embodiments, analkenyl group has 2 to 3 carbon atoms (“C₂₋₃ alkenyl”). In someembodiments, an alkenyl group has 2 carbon atoms (“C₂ alkenyl”). The oneor more carbon-carbon double bonds can be internal (such as in2-butenyl) or terminal (such as in 1-butenyl). Examples of C₂₋₄ alkenylgroups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl(C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C₂₋₆alkenyl groups include the aforementioned C₂₋₄ alkenyl groups as well aspentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additionalexamples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl(C₈), and the like. Unless otherwise specified, each instance of analkenyl group is independently unsubstituted (an “unsubstitutedalkenyl”) or substituted (a “substituted alkenyl”) with one or moresubstituents. In certain embodiments, the alkenyl group is anunsubstituted C₂₋₁₀ alkenyl. In certain embodiments, the alkenyl groupis a substituted C₂₋₁₀ alkenyl. In an alkenyl group, a C═C double bondfor which the stereochemistry is not specified (e.g., —CH═CHCH₃ or

may be an (E)- or (Z)-double bond.

The term “heteroalkenyl” refers to an alkenyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkenylgroup refers to a group having from 2 to 10 carbon atoms, at least onedouble bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkenyl”). In some embodiments, a heteroalkenyl group has2 to 9 carbon atoms at least one double bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 8 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbonatoms, at least one double bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 6 carbon atoms, at least one double bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbonatoms, at least one double bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkenyl”). In some embodiments, aheteroalkenyl group has 2 to 4 carbon atoms, at least one double bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkenyl”).In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, atleast one double bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkenyl”). In some embodiments, a heteroalkenyl group has 2to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkenyl”). Unless otherwisespecified, each instance of a heteroalkenyl group is independentlyunsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a“substituted heteroalkenyl”) with one or more substituents. In certainembodiments, the heteroalkenyl group is an unsubstituted heteroC₂₋₁₀alkenyl. In certain embodiments, the heteroalkenyl group is asubstituted heteroC₂₋₁₀ alkenyl.

The term “alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 10 carbon atoms and one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”).

In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C₂₋₅alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms(“C₂4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbonatoms (“C₂₋₃ alkynyl”). In some embodiments, an alkynyl group has 2carbon atoms (“C₂ alkynyl”). The one or more carbon-carbon triple bondscan be internal (such as in 2-butynyl) or terminal (such as in1-butynyl). Examples of C₂₋₄ alkynyl groups include, without limitation,ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄),2-butynyl (C₄), and the like. Examples of C₂₋₆ alkenyl groups includethe aforementioned C₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl(C₆), and the like. Additional examples of alkynyl include heptynyl(C₇), octynyl (C₈), and the like. Unless otherwise specified, eachinstance of an alkynyl group is independently unsubstituted (an“unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) withone or more substituents. In certain embodiments, the alkynyl group isan unsubstituted C₂₋₁₀ alkynyl. In certain embodiments, the alkynylgroup is a substituted C₂₋₁₀ alkynyl.

The term “heteroalkynyl” refers to an alkynyl group, which furtherincludes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms)selected from oxygen, nitrogen, or sulfur within (i.e., inserted betweenadjacent carbon atoms of) and/or placed at one or more terminalposition(s) of the parent chain. In certain embodiments, a heteroalkynylgroup refers to a group having from 2 to 10 carbon atoms, at least onetriple bond, and 1 or more heteroatoms within the parent chain(“heteroC₂₋₁₀ alkynyl”). In some embodiments, a heteroalkynyl group has2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatomswithin the parent chain (“heteroC₂₋₉ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₈alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbonatoms, at least one triple bond, and 1 or more heteroatoms within theparent chain (“heteroC₂₋₇ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond,and 1 or more heteroatoms within the parent chain (“heteroC₂₋₆alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbonatoms, at least one triple bond, and 1 or 2 heteroatoms within theparent chain (“heteroC₂₋₅ alkynyl”). In some embodiments, aheteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond,and 1 or 2 heteroatoms within the parent chain (“heteroC₂₋₄ alkynyl”).In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, atleast one triple bond, and 1 heteroatom within the parent chain(“heteroC₂₋₃ alkynyl”). In some embodiments, a heteroalkynyl group has 2to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatomswithin the parent chain (“heteroC₂₋₆ alkynyl”). Unless otherwisespecified, each instance of a heteroalkynyl group is independentlyunsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a“substituted heteroalkynyl”) with one or more substituents. In certainembodiments, the heteroalkynyl group is an unsubstituted heteroC₂₋₁₀alkynyl. In certain embodiments, the heteroalkynyl group is asubstituted heteroC₂₋₁₀ alkynyl.

The term “carbocyclyl” or “carbocyclic” refers to a radical of anon-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbonatoms (“C₃₋₁₄ carbocyclyl”) and zero heteroatoms in the non-aromaticring system. In some embodiments, a carbocyclyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ carbocyclyl”). In some embodiments, a carbocyclylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ carbocyclyl”). In someembodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C₃₋₇carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ringcarbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, a carbocyclylgroup has 4 to 6 ring carbon atoms (“C₄₋₆ carbocyclyl”). In someembodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C₅₋₆carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ringcarbon atoms (“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groupsinclude, without limitation, cyclopropyl (C₃), cyclopropenyl (C₃),cyclobutyl (C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl(C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and thelike. Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (Cd),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing afused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can besaturated or can contain one or more carbon-carbon double or triplebonds. “Carbocyclyl” also includes ring systems wherein the carbocyclylring, as defined above, is fused with one or more aryl or heteroarylgroups wherein the point of attachment is on the carbocyclyl ring, andin such instances, the number of carbons continue to designate thenumber of carbons in the carbocyclic ring system. Unless otherwisespecified, each instance of a carbocyclyl group is independentlyunsubstituted (an “unsubstituted carbocyclyl”) or substituted (a“substituted carbocyclyl”) with one or more substituents. In certainembodiments, the carbocyclyl group is an unsubstituted C₃₋₁₄carbocyclyl. In certain embodiments, the carbocyclyl group is asubstituted C₃₋₁₄ carbocyclyl.

In some embodiments, “carbocyclyl” is a monocyclic, saturatedcarbocyclyl group having from 3 to 14 ring carbon atoms (“C₃₋₁₄cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ringcarbon atoms (“C₃₋₁₀ cycloalkyl”). In some embodiments, a cycloalkylgroup has 3 to 8 ring carbon atoms (“C₃₋₈ cycloalkyl”). In someembodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C₃₋₆cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ringcarbon atoms (“C₄₋₆ cycloalkyl”). In some embodiments, a cycloalkylgroup has 5 to 6 ring carbon atoms (“C₅₋₆ cycloalkyl”). In someembodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C₅₋₁₀cycloalkyl”). Examples of C₅₋₆ cycloalkyl groups include cyclopentyl(C₅) and cyclohexyl (C₅). Examples of C₃₋₆ cycloalkyl groups include theaforementioned C₅₋₆ cycloalkyl groups as well as cyclopropyl (C₃) andcyclobutyl (C₄). Examples of C₃₋₈ cycloalkyl groups include theaforementioned C₃₋₆ cycloalkyl groups as well as cycloheptyl (C₇) andcyclooctyl (C₈). Unless otherwise specified, each instance of acycloalkyl group is independently unsubstituted (an “unsubstitutedcycloalkyl”) or substituted (a “substituted cycloalkyl”) with one ormore substituents. In certain embodiments, the cycloalkyl group is anunsubstituted C₃₋₁₄ cycloalkyl. In certain embodiments, the cycloalkylgroup is a substituted C₃₋₁₄ cycloalkyl.

The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to14-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). Inheterocyclyl groups that contain one or more nitrogen atoms, the pointof attachment can be a carbon or nitrogen atom, as valency permits. Aheterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”)or polycyclic (e.g., a fused, bridged or spiro ring system such as abicyclic system (“bicyclic heterocyclyl”) or tricyclic system(“tricyclic heterocyclyl”)), and can be saturated or can contain one ormore carbon-carbon double or triple bonds. Heterocyclyl polycyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system. Unless otherwise specified, eachinstance of heterocyclyl is independently unsubstituted (an“unsubstituted heterocyclyl”) or substituted (a “substitutedheterocyclyl”) with one or more substituents. In certain embodiments,the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl.In certain embodiments, the heterocyclyl group is a substituted 3-14membered heterocyclyl.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-8 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl groupis a 5-6 membered non-aromatic ring system having ring carbon atoms and1-4 ring heteroatoms, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In someembodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclylhas 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azirdinyl, oxiranyl, and thiiranyl.Exemplary 4-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, azetidinyl, oxetanyl, and thietanyl.Exemplary 5-membered heterocyclyl groups containing 1 heteroatominclude, without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl,and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining 2 heteroatoms include, without limitation, dioxolanyl,oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groupscontaining 3 heteroatoms include, without limitation, triazolinyl,oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclylgroups containing 1 heteroatom include, without limitation, piperidinyl,tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-memberedheterocyclyl groups containing 2 heteroatoms include, withoutlimitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary6-membered heterocyclyl groups containing 3 heteroatoms include, withoutlimitation, triazinyl. Exemplary 7-membered heterocyclyl groupscontaining 1 heteroatom include, without limitation, azepanyl, oxepanyland thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1heteroatom include, without limitation, azocanyl, oxecanyl andthiocanyl. Exemplary bicyclic heterocyclyl groups include, withoutlimitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl,octahydroisochromenyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, chromanyl, chromenyl,1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl,5,7-dihydro-4H-thieno[2,3-c]pyranyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl,1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g.,bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or14 π electrons shared in a cyclic array) having 6-14 ring carbon atomsand zero heteroatoms provided in the aromatic ring system (“C₆₋₁₄aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ringcarbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms(“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems whereinthe aryl ring, as defined above, is fused with one or more carbocyclylor heterocyclyl groups wherein the radical or point of attachment is onthe aryl ring, and in such instances, the number of carbon atomscontinue to designate the number of carbon atoms in the aryl ringsystem. Unless otherwise specified, each instance of an aryl group isindependently unsubstituted (an “unsubstituted aryl”) or substituted (a“substituted aryl”) with one or more substituents. In certainembodiments, the aryl group is an unsubstituted C₆₋₁₄ aryl. In certainembodiments, the aryl group is a substituted C₆₋₁₄ aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by an aryl group, wherein the point of attachment is on thealkyl moiety.

The term “heteroaryl” refers to a radical of a 5-14 membered monocyclicor polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system(e.g., having 6, 10, or 14 t electrons shared in a cyclic array) havingring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ringsystem, wherein each heteroatom is independently selected from nitrogen,oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groupsthat contain one or more nitrogen atoms, the point of attachment can bea carbon or nitrogen atom, as valency permits. Heteroaryl polycyclicring systems can include one or more heteroatoms in one or both rings.“Heteroaryl” includes ring systems wherein the heteroaryl ring, asdefined above, is fused with one or more carbocyclyl or heterocyclylgroups wherein the point of attachment is on the heteroaryl ring, and insuch instances, the number of ring members continue to designate thenumber of ring members in the heteroaryl ring system. “Heteroaryl” alsoincludes ring systems wherein the heteroaryl ring, as defined above, isfused with one or more aryl groups wherein the point of attachment iseither on the aryl or heteroaryl ring, and in such instances, the numberof ring members designates the number of ring members in the fusedpolycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groupswherein one ring does not contain a heteroatom (e.g., indolyl,quinolinyl, carbazolyl, and the like) the point of attachment can be oneither ring, i.e., either the ring bearing a heteroatom (e.g.,2-indolyl) or the ring that does not contain a heteroatom (e.g.,5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unlessotherwise specified, each instance of a heteroaryl group isindependently unsubstituted (an “unsubstituted heteroaryl”) orsubstituted (a “substituted heteroaryl”) with one or more substituents.In certain embodiments, the heteroaryl group is an unsubstituted 5-14membered heteroaryl. In certain embodiments, the heteroaryl group is asubstituted 5-14 membered heteroaryl.

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include,without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary5-membered heteroaryl groups containing 2 heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing 3heteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4heteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing 1 heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, andpyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4heteroatoms include, without limitation, triazinyl and tetrazinyl,respectively. Exemplary 7-membered heteroaryl groups containing 1heteroatom include, without limitation, azepinyl, oxepinyl, andthiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, withoutlimitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, andpurinyl. Exemplary 6,6-bicyclic heteroaryl groups include, withoutlimitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplarytricyclic heteroaryl groups include, without limitation,phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl,phenoxazinyl and phenazinyl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl groupsubstituted by a heteroaryl group, wherein the point of attachment is onthe alkyl moiety.

Affixing the suffix “-ene” to a group indicates the group is a divalentmoiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene isthe divalent moiety of alkenyl, alkynylene is the divalent moiety ofalkynyl, heteroalkylene is the divalent moiety of heteroalkyl,heteroalkenylene is the divalent moiety of heteroalkenyl,heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclyleneis the divalent moiety of carbocyclyl, heterocyclylene is the divalentmoiety of heterocyclyl, arylene is the divalent moiety of aryl, andheteroarylene is the divalent moiety of heteroaryl.

A group is optionally substituted unless expressly provided otherwise.The term “optionally substituted” refers to being substituted orunsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl groups are optionally substituted. “Optionallysubstituted” refers to a group which may be substituted or unsubstituted(e.g., “substituted” or “unsubstituted” alkyl, “substituted” or“unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl,“substituted” or “unsubstituted” heteroalkyl, “substituted” or“unsubstituted” heteroalkenyl, “substituted” or “unsubstituted”heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl,“substituted” or “unsubstituted” heterocyclyl, “substituted” or“unsubstituted” aryl or “substituted” or “unsubstituted” heteroarylgroup). In general, the term “substituted” means that at least onehydrogen present on a group is replaced with a permissible substituent,e.g., a substituent which upon substitution results in a stablecompound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position. The term“substituted” is contemplated to include substitution with allpermissible substituents of organic compounds, and includes any of thesubstituents described herein that results in the formation of a stablecompound. The present invention contemplates any and all suchcombinations in order to arrive at a stable compound. For purposes ofthis invention, heteroatoms such as nitrogen may have hydrogensubstituents and/or any suitable substituent as described herein whichsatisfy the valencies of the heteroatoms and results in the formation ofa stable moiety. The invention is not intended to be limited in anymanner by the exemplary substituents described herein.

Exemplary carbon atom substituents include, but are not limited to,halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(aa)—, —ON(R^(bb))₂,—N(R^(bb))₂, —N(R^(bb))₃ ⁺X⁻, —N(OR^(cc))R^(bb), —SH, —SR^(aa)—,—SSR^(cc), —C(═O)R^(aa), —CO₂H, —CHO, —C(OR^(cc))₂, —CO₂R^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —C(═O)N(R^(bb))₂, —OC(═O)N(R^(bb))₂,—NR^(bb)C(═O)R^(aa)—, —NR^(bb)CO₂R^(aa)—, —NR^(bb)C(═O)N(R^(bb))₂,—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa), —OC(═NR^(bb))R^(aa),—OC(═NR^(bb))OR^(aa), —C(═NR^(bb))N(R^(bb))₂, —OC(═NR^(bb))N(R^(bb))₂,—NR^(bb)C(═NR^(bb))N(R^(bb))₂, —C(═O)NR^(bb)SO₂R^(aa),—NR^(bb)SO₂R^(aa), —SO₂N(R^(bb))₂, —S₂R^(aa), —SO₂OR^(aa), —OSO₂R^(aa),—S(═O)R^(aa), —OS(═O)R^(aa), —Si(R^(aa))₃,—OSi(R^(aa))₃—C(═S)N(R^(bb))₂, —C(═O)SR^(aa), —C(═S)SR^(aa),—SC(═S)SR^(aa), —SC(═O)SR^(aa), —OC(═O)SR^(aa), —SC(═O)OR^(aa),—SC(═O)R^(aa), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —OP(═O)(R^(aa))₂,—OP(═O)(OR^(cc))₂, —P(═O)(N(R^(bb))₂)₂, —OP(═O)(N(R^(bb))₂)₂,—NR^(bb)P(═O)(R^(aa))₂, —NR^(bb)P(═O)(OR^(cc))₂,—NR^(bb)P(═O)(N(R^(bb))₂)₂, —P(R^(cc))₂, —P(OR^(cc))₂, —P(R^(cc))₃ ⁺X⁻,—P(OR^(cc))₃ ⁺X⁻, —P(R^(cc))₄, —P(OR^(cc))₄, —OP(R^(cc))₂, —OP(R^(cc))₃⁺X⁻, —OP(OR^(cc))₂, —OP(OR^(cc))₃ ⁺X⁻, —OP(R^(cc))₄, —OP(OR^(cc))₄,—B(R^(aa))₂, —B(OR^(cc))₂, —BR^(aa)(OR^(cc)), C₁₋₁₀ alkyl, C₁₋₁₀perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl,heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, whereineach alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 Rd groups; wherein X⁻ is acounterion;

or two geminal hydrogens on a carbon atom are replaced with the group═O, ═S, ═NN(R^(bb))₂, ═NNR^(bb)C(═O)R^(aa)—, ═NNR^(bb)C(═O)OR^(aa),═NNR^(bb)S(═O)₂R^(aa), ═NR^(bb), or ═NOR^(cc); each instance of R^(aa)is, independently, selected from C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀alkenyl,heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄aryl, and 5-14 membered heteroaryl, or two R^(aa) groups are joined toform a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl isindependently substituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups;

each instance of R^(bb) is, independently, selected from hydrogen, —OH,—OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa), —C(═O)N(R^(cc))₂, —CO₂R^(aa),—SO₂R^(aa), —C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(Rc)₂,—SO₂Rc, —SO₂OR^(cc), —SOR^(aa), —C(═S)N(Rc)₂, —C(═O)SR^(cc),—C(═S)SR^(cc), —P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, —P(═O)(N(R^(cc))₂)₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀alkyl, heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(bb) groups are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups; wherein X⁻ is acounterion;

each instance of R^(cc) is, independently, selected from hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀ carbocyclyl, 3-14membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or twoR^(cc) groups are joined to form a 3-14 membered heterocyclyl or 5-14membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl,aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or5 R^(dd) groups;

each instance of R^(dd) is, independently, selected from halogen, —CN,—NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^(ee), —ON(R^(ff))₂, —N(R^(ff))₂,—N(R^(ff))₃ ⁺X⁻, —N(OR^(ee))R^(ff), —SH, —SR^(ee), —SSR^(ee),—C(═O)R^(ee), —CO₂H, —CO₂R^(ee), —OC(═O)R^(ee), —OCO₂R^(ee),—C(═O)N(R^(ff))₂, —OC(═O)N(R^(ff))₂, —NR^(ff)C(═O)R^(ee),—NR^(ff)CO₂R^(ee), —NR^(ff)C(═O)N(R^(ff))₂, —C(═NR^(ff))OR^(ee),—OC(═NR^(ff))R^(ee), —OC(═NR^(ff))OR^(ee), —C(═NR^(ee))N^(ff)(R^(ff))₂,—NR^(ff)C(═NR^(ff))N(R^(ff))₂, —NR^(ff)SO₂R^(ee), —SO₂N(R^(ff))₂,—SO₂R^(ee), —SO₂R^(ee), —OSO₂R^(ee), —S(═O)R^(ee), —Si(R^(ee))₃,—OSi(R^(ee))₃, —C(═S)N(R^(ff))₂, —C(═O)SR^(ee), —C(═S)SR^(ee),—SC(═S)SR^(ee), —P(═O)(OR^(ee))₂, —P(═O)(R^(ee))₂, —OP(═O)(R^(ee))₂,—OP(═O)(OR^(ee))₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, 3-10 membered heterocyclyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups, or two geminal R^(dd) substituents can be joined to form ═O or═S; wherein X⁻ is a counterion;

each instance of R^(ee) is, independently, selected from C₁₋₆ alkyl,C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆ alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆ alkynyl, C₃₋₁₀ carbocyclyl, C₆₋₁₀ aryl,3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein eachalkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(gg) groups;

each instance of R^(ff) is, independently, selected from hydrogen, C₁₋₆alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, heteroC₁₋₆alkyl,heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀ carbocyclyl, 3-10 memberedheterocyclyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl, or two R^(ff)groups are joined to form a 3-10 membered heterocyclyl or 5-10 memberedheteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, andheteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^(gg)groups; and

each instance of R^(gg) is, independently, halogen, —CN, —NO₂, —N₃,—SO₂H, —SO₃H, —OH, —OC₁₋₆ alkyl, —ON(C₁₋₆ alkyl)₂, —N(C₁₋₆ alkyl)₂,—N(C₁₋₆ alkyl)₃ ⁺X⁻, —NH(C₁₋₆ alkyl)₂ ⁺X⁻, —NH₂(C₁₋₆ alkyl)₊X⁻, —NH₃⁺X⁻, —N(OC₁₋₆ alkyl)(C₁₋₆ alkyl), —N(OH)(C₁₋₆ alkyl), —NH(OH), —SH,—SC₁₋₆ alkyl, —SS(C₁₋₆ alkyl), —C(═O)(C₁₋₆ alkyl), —CO₂H, —CO₂(C₁₋₆alkyl), —OC(═O)(C₁₋₆ alkyl), —OCO₂(C₁₋₆ alkyl), —C(═O)NH₂, —C(═O)N(C₁₋₆alkyl)₂, —OC(═O)NH(C₁₋₆ alkyl), —NHC(═O)(C₁₋₆ alkyl), —N(C₁₋₆alkyl)C(═O)(C₁₋₆ alkyl), —NHCO₂(C₁₋₆ alkyl), —NHC(═O)N(C₁₋₆ alkyl)₂,—NHC(═O)NH(C₁₋₆ alkyl), —NHC(═O)NH₂, —C(═NH)O(C₁₋₆ alkyl), —OC(═NH)(C₁₋₆alkyl), —OC(═NH)OC₁₋₆ alkyl, —C(═NH)N(C₁₋₆ alkyl)₂, —C(═NH)NH(C₁₋₆alkyl), —C(═NH)NH₂, —OC(═NH)N(C₁₋₆ alkyl)₂, —OC(NH)NH(C₁₋₆ alkyl),—OC(NH)NH₂, —NHC(NH)N(C₁₋₆ alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C₁₋₆ alkyl),—SO₂N(C₁₋₆ alkyl)₂, —SO₂NH(C₁₋₆ alkyl), —SO₂NH₂, —SO₂C₁₋₆ alkyl,—SO₂OC₁₋₆ alkyl, —OSO₂C₁₋₆ alkyl, —SOC₁₋₆ alkyl, —Si(C₁₋₆ alkyl)₃,—OSi(C₁₋₆ alkyl)₃, —C(═S)N(C₁₋₆ alkyl)₂, C(═S)NH(C₁₋₆ alkyl), C(═S)NH₂,—C(═O)S(C₁₋₆ alkyl), —C(═S)SC₁₋₆ alkyl, —SC(═S)SC₁₋₆ alkyl, —P(═O)(OC₁₋₆alkyl)₂, —P(═O)(C₁₋₆ alkyl)₂, —OP(═O)(C₁₋₆ alkyl)₂, —OP(═O)(OC₁₋₆alkyl)₂, C₁₋₆ alkyl, C₁₋₆ perhaloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,heteroC₁₋₆alkyl, heteroC₂₋₆alkenyl, heteroC₂₋₆alkynyl, C₃₋₁₀carbocyclyl, C₆₋₁₀ aryl, 3-10 membered heterocyclyl, 5-10 memberedheteroaryl; or two geminal R^(gg) substituents can be joined to form ═Oor ═S; wherein X⁻ is a counterion.

The term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine(chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

The term “hydroxyl” or “hydroxy” refers to the group —OH. The term“substituted hydroxyl” or “substituted hydroxyl,” by extension, refersto a hydroxyl group wherein the oxygen atom directly attached to theparent molecule is substituted with a group other than hydrogen, andincludes groups selected from —OR^(aa), —ON(R^(bb))₂, —OC(═O)SR^(aa),—OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(Rb)₂, —OC(═NR^(bb))R^(aa),OC(═NR^(bb))OR^(aa), —OC(═NR^(bb))N(R^(bb))₂, —OS(═O)R^(aa), —OSO₂Ra,—OSi(R^(aa))₃, —OP(R^(cc))₂, —OP(R^(cc))₃ ⁺X⁻, —OP(OR^(cc))₂,—OP(OR^(cc))₃ ⁺X⁻, —OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, and—OP(═O)(N(Rb))₂, wherein X⁻, R^(aa), R^(bb), and R^(cc) are as definedherein.

The term “amino” refers to the group —NH₂. The term “substituted amino,”by extension, refers to a monosubstituted amino, a disubstituted amino,or a trisubstituted amino. In certain embodiments, the “substitutedamino” is a monosubstituted amino or a disubstituted amino group.

The term “monosubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith one hydrogen and one group other than hydrogen, and includes groupsselected from —NH(R^(bb)), —NHC(═O)R^(aa)—, —NHCO₂R^(aa),—NHC(═O)N(R^(bb))₂, —NHC(═NR^(bb))N(R^(bb))₂, —NHSO₂R^(aa),—NHP(═O)(OR^(cc))₂, and —NHP(═O)(N(R^(bb))₂)₂, wherein R^(aa), R^(bb)and R^(cc) are as defined herein, and wherein R^(bb) of the group—NH(R^(bb)) is not hydrogen.

The term “disubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith two groups other than hydrogen, and includes groups selected from—N(R^(bb))₂, —NR^(bb)C(═O)R^(aa), —NR^(bb)CO₂R^(aa),—NR^(bb)C(═O)N(R^(bb))₂, —NR^(bb)C(═NR^(bb))N(R^(bb))₂,—NR^(bb)SO₂R^(aa)—, —NR^(bb)P(═O)(OR^(cc))₂, and—NR^(bb)P(═O)(N(R^(bb))₂)₂, wherein R^(aa), R^(bb), and R^(cc) are asdefined herein, with the proviso that the nitrogen atom directlyattached to the parent molecule is not substituted with hydrogen.

The term “trisubstituted amino” refers to an amino group wherein thenitrogen atom directly attached to the parent molecule is substitutedwith three groups, and includes groups selected from —N(R^(bb))₃ and—N(R^(bb))₃ ⁺X⁻, wherein R^(bb) and X⁻ are as defined herein.

The term “sulfonyl” refers to a group selected from —SO₂N(R^(bb))₂,—SO₂R^(aa), and —SO₂OR^(aa), wherein R^(aa) and R^(bb) are as definedherein.

The term “acyl” refers to a group having the general formula—C(═O)R^(X1), —C(═O)OR^(X1), —C(═O)—O—C(═O)R^(X1), —C(═O)SR^(X1),—C(═O)N(R^(X1))₂, —C(═S)R^(X1), —C(═S)N(R^(X1))₂, and —C(═S)S(R^(X1)),—C(═NR^(X1))R^(X1), —C(═NR^(X1))OR^(X1), —C(═NR^(X1))SR^(X1), and—C(═NR^(X1))N(R^(X1))₂, wherein R^(X1) is hydrogen; halogen; substitutedor unsubstituted hydroxyl; substituted or unsubstituted thiol;substituted or unsubstituted amino; substituted or unsubstituted acyl,cyclic or acyclic, substituted or unsubstituted, branched or unbranchedaliphatic; cyclic or acyclic, substituted or unsubstituted, branched orunbranched heteroaliphatic; cyclic or acyclic, substituted orunsubstituted, branched or unbranched alkyl; cyclic or acyclic,substituted or unsubstituted, branched or unbranched alkenyl;substituted or unsubstituted alkynyl; substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, aliphaticoxy,heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy,aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy,arylthioxy, heteroarylthioxy, mono- or di-aliphaticamino, mono- ordi-heteroaliphaticamino, mono- or di-alkylamino, mono- ordi-heteroalkylamino, mono- or di-arylamino, or mono- ordi-heteroarylamino; or two R^(X1) groups taken together form a 5- to6-membered heterocyclic ring. Exemplary acyl groups include aldehydes(—CHO), carboxylic acids (—CO₂H), ketones, acyl halides, esters, amides,imines, carbonates, carbamates, and ureas. Acyl substituents include,but are not limited to, any of the substituents described herein, thatresult in the formation of a stable moiety (e.g., aliphatic, alkyl,alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl,oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl,thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino,heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl,aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy,heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy,heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like,each of which may or may not be further substituted).

The term “carbonyl” refers a group wherein the carbon directly attachedto the parent molecule is sp² hybridized, and is substituted with anoxygen, nitrogen or sulfur atom, e.g., a group selected from ketones(—C(═O)R^(aa)), carboxylic acids (—CO₂H), aldehydes (—CHO), esters(—CO₂R^(aa), —C(═O)SR^(aa), —C(═S)SR^(aa)), amides (—C(═O)N(R^(bb))₂,—C(═O)NR^(bb)SO₂R^(aa), —C(═S)N(R^(bb))₂), and imines(—C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa)), —C(═NR^(bb))N(R^(bb))₂),wherein R^(aa) and R^(bb) are as defined herein.

The term “oxo” refers to the group ═O, and the term “thiooxo” refers tothe group ═S.

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quaternary nitrogen atoms.Exemplary nitrogen atom substituents include, but are not limited to,hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R, —C(═NR^(bb))R^(aa),—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)(OR^(cc))₂, —P(═O)(R^(aa))₂, —P(═O)(N(R^(cc))₂)₂, C₁₋₁₀ alkyl,C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, heteroC₁₋₁₀alkyl,heteroC₂₋₁₀alkenyl, heteroC₂₋₁₀alkynyl, C₃₋₁₀ carbocyclyl, 3-14 memberedheterocyclyl, C₆₋₁₄ aryl, and 5-14 membered heteroaryl, or two R^(cc)groups attached to an N atom are joined to form a 3-14 memberedheterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentlysubstituted with 0, 1, 2, 3, 4, or 5 R^(dd) groups, and wherein R^(aa),R^(bb), R^(cc) and R^(dd) are as defined above.

In certain embodiments, the substituent present on the nitrogen atom isan nitrogen protecting group (also referred to herein as an “aminoprotecting group”). Nitrogen protecting groups include, but are notlimited to, —OH, —OR^(aa), —N(R^(cc))₂, —C(═O)R^(aa), —C(═O)N(R^(cc))₂,—CO₂R^(aa), —SO₂R^(aa), —C(═NR^(cc))R^(aa), —C(═NR^(cc))OR^(aa),—C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc), —SO₂OR^(cc),—SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc), C₁₋₁₀ alkyl(e.g., aralkyl, heteroaralkyl), C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,heteroC₁₋₁₀ alkyl, heteroC₂₋₁₀ alkenyl, heteroC₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl,heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined herein. Nitrogen protecting groups are well known in the art andinclude those described in detail in Protecting Groups in OrganicSynthesis, T. W. Greene and P. G. M. Wuts, 3^(rd) edition, John Wiley &Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g.,—C(═O)R^(aa)) include, but are not limited to, formamide, acetamide,chloroacetamide, trichloroacetamide, trifluoroacetamide,phenylacetamide, 3-phenylpropanamide, picolinamide,3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide,p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide,acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide,3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,2-methyl-2-(o-nitrophenoxy)propanamide,2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethioninederivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g.,—C(═O)OR^(aa)) include, but are not limited to, methyl carbamate, ethylcarbamate, 9-fluorenylmethyl carbamate (Fmoc),9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethylcarbamate,2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methylcarbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate(Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethylcarbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate,1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC),1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC),1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethylcarbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc),vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallylcarbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate(Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzylcarbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzylcarbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate,2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate,2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc),2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate(Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc),1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate,p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate,2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate,3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzylcarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentylcarbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate,2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate,isobutyl carbamate, isonicotinyl carbamate,p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate,1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate,1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate,p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate,4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzylcarbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g.,—S(═O)₂R^(aa)) include, but are not limited to, p-toluenesulfonamide(Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide(Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb),2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide(Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide(Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide,4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to,phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacylderivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanylderivative, N-acetylmethionine derivative,4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts),N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole,N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE),5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine,N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammoniumsalts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),N-9-phenylfluorenylamine (PhF),N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm),N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine,N-benzylideneamine, N-p-methoxybenzylideneamine,N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine,N-p-nitrobenzylideneamine, N-salicylideneamine,N-5-chlorosalicylideneamine,N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,N-borane derivative, N-diphenylborinic acid derivative,N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate,N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide,diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt),diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzylphosphoramidate, diphenyl phosphoramidate, benzenesulfenamide,o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide,pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide,triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). Incertain embodiments, a nitrogen protecting group described herein is Bn,Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts.

In certain embodiments, the substituent present on an oxygen atom is anoxygen protecting group (also referred to herein as an “hydroxylprotecting group”). Oxygen protecting groups include, but are notlimited to, —R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa),—CO₂R^(aa), —C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, wherein X⁻,R^(aa), R^(bb), and R^(cc) are as defined herein. Oxygen protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference.

Exemplary oxygen protecting groups include, but are not limited to,methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl,(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR),tetrahydropyranyl (THP), 3-bromotetrahydropyranyl,tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl(MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl,p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido,diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl,triphenylmethyl, α-naphthyldiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl(TMS), triethylsilyl (TES), triisopropylsilyl (TIPS),dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS),dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl(TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl,diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate,benzoylformate, acetate, chloroacetate, dichloroacetate,trichloroacetate, trifluoroacetate, methoxyacetate,triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate,3-phenylpropionate, 4-oxopentanoate (levulinate),4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethylcarbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate(Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc),isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate(BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzylcarbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate,p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththylcarbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate(Ts). In certain embodiments, an oxygen protecting group describedherein is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn,allyl, acetyl, pivaloyl, or benzoyl.

In certain embodiments, the substituent present on a sulfur atom is asulfur protecting group (also referred to as a “thiol protectinggroup”). Sulfur protecting groups include, but are not limited to,—R^(aa), —N(R^(bb))₂, —C(═O)SR^(aa), —C(═O)R^(aa), —CO₂R^(aa),—C(═O)N(R^(bb))₂, —C(═NR^(bb))R^(aa), —C(═NR^(bb))OR^(aa),—C(═NR^(bb))N(R^(bb))₂, —S(═O)R^(aa), —SO₂R^(aa), —Si(R^(aa))₃,—P(R^(cc))₂, —P(R^(cc))₃ ⁺X⁻, —P(OR^(cc))₂, —P(OR^(cc))₃ ⁺X⁻,—P(═O)(R^(aa))₂, —P(═O)(OR^(cc))₂, and —P(═O)(N(R^(bb))₂)₂, whereinR^(aa), R^(bb), and R^(cc) are as defined herein. Sulfur protectinggroups are well known in the art and include those described in detailin Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.Wuts, 3^(rd) edition, John Wiley & Sons, 1999, incorporated herein byreference. In certain embodiments, a sulfur protecting group describedherein is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl,2-pyridine-sulfenyl, or triphenylmethyl.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a positively charged group in order to maintainelectronic neutrality. An anionic counterion may be monovalent (i.e.,including one formal negative charge). An anionic counterion may also bemultivalent (i.e., including more than one formal negative charge), suchas divalent or trivalent. Exemplary counterions include halide ions(e.g., F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HCO₃ ⁻, HSO₄ ⁻,sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,glycolate, gluconate, and the like), BF₄ ⁻, PF₄ ⁻, PF₆ ⁻AsF₆ ⁻, SbF₆ ⁻,B[3,5-(CF₃)₂C₆H₃]₄]⁻, B(C₆F₅)₄ ⁻, BPh₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, and carboraneanions (e.g., CB₁₁H₁₂ ⁻ or (HCB₁₁Me₅Br₆)⁻). Exemplary counterions whichmay be multivalent include CO₃ ²⁻, HPO₄ ²⁻, P₄ ³⁻, B₄O₇ ²⁻, SO₄ ²⁻, S₂O₃²⁻, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate,malate, malonate, gluconate, succinate, glutarate, adipate, pimelate,suberate, azelate, sebacate, salicylate, phthalates, aspartate,glutamate, and the like), and carboranes.

As used herein, a “leaving group” (LG) is an art-understood termreferring to a molecular fragment that departs with a pair of electronsin heterolytic bond cleavage, wherein the molecular fragment is an anionor neutral molecule. As used herein, a leaving group can be an atom or agroup capable of being displaced by a nucleophile. See, for example,Smith, March Advanced Organic Chemistry 6th ed. (501-502). Exemplaryleaving groups include, but are not limited to, halo (e.g., chloro,bromo, iodo) and activated substituted hydroxyl groups (e.g.,—OC(═O)SR^(aa), —OC(═O)R^(aa), —OCO₂R^(aa), —OC(═O)N(R^(bb))₂,—OC(═NR^(bb))R^(aa), —OC(═NR^(bb))OR—, —OC(═NR^(bb))N(R^(bb))₂,—OS(═O)R^(aa), —OSO₂R^(aa), —OP(R^(cc))₂, —OP(R^(cc))₃, —OP(═O)₂R^(aa),—OP(═O)(R^(aa))₂, —OP(═O)(OR^(cc))₂, —OP(═O)₂N(R^(bb))₂, and—OP(═O)(NR^(bb))₂, wherein R^(aa), R^(bb), and R^(cc) are as definedherein). Examples of suitable leaving groups include, but are notlimited to, halides (such as chloride, bromide, or iodide),alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy,arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy,aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, haloformates, —NO₂,trialkylammonium, and aryliodonium salts. In certain embodiments, theleaving group is a sulfonic acid ester. In certain embodiments, thesulfonic acid ester comprises the formula —OSO₂R^(LG1) wherein R^(LG1)is selected from the group consisting alkyl optionally, alkenyloptionally substituted, heteroalkyl optionally substituted, aryloptionally substituted, heteroaryl optionally substituted, arylalkyloptionally substituted, and heterarylalkyl optionally substituted. Incertain embodiments, R^(LG1) is substituted or unsubstituted C₁-C₆alkyl. In certain embodiments, R^(LG1) is methyl. In certainembodiments, R^(LG1) is —CF₃. In certain embodiments, R^(LG1) issubstituted or unsubstituted aryl. In certain embodiments, R^(LG1) issubstituted or unsubstituted phenyl. In certain embodiments R^(LG1) is:

As used herein, use of the phrase “at least one instance” refers to 1,2, 3, 4, or more instances, but also encompasses a range, e.g., forexample, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to3, or from 3 to 4 instances, inclusive.

A “non-hydrogen group” refers to any group that is defined for aparticular variable that is not hydrogen.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other definitions

As used herein, the term “salt” refers to any and all salts, andencompasses pharmaceutically acceptable salts.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein byreference. Pharmaceutically acceptable salts of the compounds of thisinvention include those derived from suitable inorganic and organicacids and bases. Examples of pharmaceutically acceptable, nontoxic acidaddition salts are salts of an amino group formed with inorganic acids,such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuricacid, and perchloric acid or with organic acids, such as acetic acid,oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, ormalonic acid or by using other methods known in the art such as ionexchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium, and N⁺(C₁₋₄ alkyl)₄ ⁻ salts.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound, or a salt thereof,that are associated with a solvent, usually by a solvolysis reaction.This physical association may include hydrogen bonding. Conventionalsolvents include water, methanol, ethanol, acetic acid, DMSO, THF,diethyl ether, and the like. The compounds described herein may beprepared, e.g., in crystalline form, and may be solvated. Suitablesolvates include pharmaceutically acceptable solvates and furtherinclude both stoichiometric solvates and non-stoichiometric solvates. Incertain instances, the solvate will be capable of isolation, forexample, when one or more solvent molecules are incorporated in thecrystal lattice of a crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Representative solvates includehydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water.Typically, the number of the water molecules contained in a hydrate of acompound is in a definite ratio to the number of the compound moleculesin the hydrate. Therefore, a hydrate of a compound may be represented,for example, by the general formula R.x H₂O, wherein R is the compound,and x is a number greater than 0. A given compound may form more thanone type of hydrate, including, e.g., monohydrates (x is 1), lowerhydrates (x is a number greater than 0 and smaller than 1, e.g.,hemihydrates (R-0.5 H₂O)), and polyhydrates (x is a number greater than1, e.g., dihydrates (R-2 H₂O) and hexahydrates (R.6 H₂O)).

The term “tautomers” or “tautomeric” refers to two or moreinterconvertible compounds resulting from at least one formal migrationof a hydrogen atom and at least one change in valency (e.g., a singlebond to a double bond, a triple bond to a single bond, or vice versa).The exact ratio of the tautomers depends on several factors, includingtemperature, solvent, and pH. Tautomerizations (i.e., the reactionproviding a tautomeric pair) may catalyzed by acid or base. Exemplarytautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim,enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

The term “polymorph” refers to a crystalline form of a compound (or asalt, hydrate, or solvate thereof). All polymorphs have the sameelemental composition. Different crystalline forms usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Recrystallization solvent, rate ofcrystallization, storage temperature, and other factors may cause onecrystal form to dominate. Various polymorphs of a compound can beprepared by crystallization under different conditions.

The term “co-crystal” refers to a crystalline structure composed of atleast two components. In certain embodiments, a co-crystal contains acompound of the present invention and one or more other component,including but not limited to, atoms, ions, molecules, or solventmolecules. In certain embodiments, a co-crystal contains a compound ofthe present invention and one or more solvent molecules. In certainembodiments, a co-crystal contains a compound of the present inventionand one or more acid or base. In certain embodiments, a co-crystalcontains a compound of the present invention and one or more componentsrelated to said compound, including not limited to, an isomer, tautomer,salt, solvate, hydrate, synthetic precursor, synthetic derivative,fragment or impurity of said compound.

The term “prodrugs” refers to compounds that have cleavable groups andbecome by solvolysis or under physiological conditions the compoundsdescribed herein, which are pharmaceutically active in vivo. Suchexamples include, but are not limited to, choline ester derivatives andthe like, N-alkylmorpholine esters and the like. Other derivatives ofthe compounds described herein have activity in both their acid and acidderivative forms, but in the acid sensitive form often offer advantagesof solubility, tissue compatibility, or delayed release in the mammalianorganism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well knownto practitioners of the art, such as, for example, esters prepared byreaction of the parent acid with a suitable alcohol, or amides preparedby reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides. Simplealiphatic or aromatic esters, amides, and anhydrides derived from acidicgroups pendant on the compounds described herein are particularprodrugs. In some cases it is desirable to prepare double ester typeprodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkyl esters ofthe compounds described herein may be preferred.

The term “small molecule” refers to molecules, whethernaturally-occurring or artificially created (e.g., via chemicalsynthesis) that have a relatively low molecular weight. Typically, asmall molecule is an organic compound (i.e., it contains carbon). Thesmall molecule may contain multiple carbon-carbon bonds, stereocenters,and other functional groups (e.g., amines, hydroxyl, carbonyls, andheterocyclic rings, etc.). In certain embodiments, the molecular weightof a small molecule is at most about 1,000 g/mol, at most about 900g/mol, at most about 800 g/mol, at most about 700 g/mol, at most about600 g/mol, at most about 500 g/mol, at most about 400 g/mol, at mostabout 300 g/mol, at most about 200 g/mol, or at most about 100 g/mol. Incertain embodiments, the molecular weight of a small molecule is atleast about 100 g/mol, at least about 200 g/mol, at least about 300g/mol, at least about 400 g/mol, at least about 500 g/mol, at leastabout 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, orat least about 900 g/mol, or at least about 1,000 g/mol. Combinations ofthe above ranges (e.g., at least about 200 g/mol and at most about 500g/mol) are also possible. In certain embodiments, the small molecule isa therapeutically active agent such as a drug (e.g., a molecule approvedby the U.S. Food and Drug Administration as provided in the Code ofFederal Regulations (C.F.R.)). The small molecule may also be complexedwith one or more metal atoms and/or metal ions. In this instance, thesmall molecule is also referred to as a “small organometallic molecule.”Preferred small molecules are biologically active in that they produce abiological effect in animals, preferably mammals, more preferablyhumans. Small molecules include, but are not limited to, radionuclidesand imaging agents. In certain embodiments, the small molecule is adrug. Preferably, though not necessarily, the drug is one that hasalready been deemed safe and effective for use in humans or animals bythe appropriate governmental agency or regulatory body. For example,drugs approved for human use are listed by the FDA under 21 C.F.R. §§330.5, 331 through 361, and 440 through 460, incorporated herein byreference; drugs for veterinary use are listed by the FDA under 21C.F.R. §§ 500 through 589, incorporated herein by reference. All listeddrugs are considered acceptable for use in accordance with the presentdisclosure.

A “protein,” “peptide,” or “polypeptide” comprises a polymer of aminoacid residues linked together by peptide bonds and refers to proteins,polypeptides, and peptides of any size, structure, or function.Typically, a protein will be at least three amino acids long. A proteinmay refer to an individual protein or a collection of proteins. Proteinsdescribed herein preferably contain only natural amino acids, althoughnon-natural amino acids (i.e., compounds that do not occur in nature butthat can be incorporated into a polypeptide chain) and/or amino acidanalogs as are known in the art may alternatively be employed. Also, oneor more of the amino acids in a protein may be modified, for example, bythe addition of a chemical entity such as a carbohydrate group, ahydroxyl group, a phosphate group, a farnesyl group, an isofarnesylgroup, a fatty acid group, a linker for conjugation orfunctionalization, or other modification. A protein may also be a singlemolecule or may be a multi-molecular complex. A protein may be afragment of a naturally occurring protein or peptide. A protein may benaturally occurring, recombinant, synthetic, or any combination ofthese.

The term “gene” refers to a nucleic acid fragment that expresses aspecific protein, including regulatory sequences preceding (5′non-codingsequences) and following (3′non-coding sequences) the coding sequence.“Native gene” refers to a gene as found in nature with its ownregulatory sequences. “Chimeric gene” or “chimeric construct” refers toany gene or a construct, not a native gene, comprising regulatory andcoding sequences that are not found together in nature. Accordingly, achimeric gene or chimeric construct may comprise regulatory sequencesand coding sequences that are derived from different sources, orregulatory sequences and coding sequences derived from the same source,but arranged in a manner different than that found in nature.“Endogenous gene” refers to a native gene in its natural location in thegenome of an organism. A “foreign” gene refers to a gene not normallyfound in the host organism, but which is introduced into the hostorganism by gene transfer. Foreign genes can comprise native genesinserted into a non-native organism, or chimeric genes. A “transgene” isa gene that has been introduced into the genome by a transformationprocedure.

The term “histone” refers to highly alkaline proteins found ineukaryotic cell nuclei that package and order the DNA into structuralunits called nucleosomes. They are the chief protein components ofchromatin, acting as spools around which DNA winds, and play a role ingene regulation. In certain embodiments, the histone is histone H1(e.g., histone H1F, histone H1H1). In certain embodiments, the histoneis histone H2A (e.g., histone H2AF, histone H2A1, histone H2A2). Incertain embodiments, the histone is histone H2B (e.g., histone H2BF,histone H2B1, histone H2B2). In certain embodiments, the histone ishistone H3 (e.g., histone H3A1, histone H3A2, histone H3A3). In certainembodiments, the histone is histone H4 (e.g., histone H41, histone H44).

The term “bromodomain” refers to a protein domain that recognizesacetylated lysine residues such as those on the N-terminal tails ofhistones. In certain embodiments, a bromodomain of a BET proteincomprises about 110 amino acids and shares a conserved fold comprising aleft-handed bundle of four alpha helices linked by diverse loop regionsthat interact with chromatin. In certain embodiments, the bromodomain isASH1L (GenBank ID: gil18922081), ATAD2 (GenBank ID: gil124497618), BAZ2B(GenBank ID: gil7304923), BRD1 (GenBank ID: gil11321642), BRD2(1)(GenBank ID: gil4826806), BRD2(2) (GenBank ID: gil14826806), BRD3(1)(GenBank ID: gil11067749), BRD3(2) (GenBank ID: gil11067749), BRD4(1)(GenBank ID: gil19718731), BRD4(2) (GenBank ID: gil19718731), BRD9(GenBank ID: gil57770383), BRDT(1) (GenBank ID: gil46399198), BRPF1(GenBank ID: gil51173720), CECR2 (GenBank ID: gil148612882), CREBBP(GenBank ID: gil14758056), EP300 (GenBank ID: gil50345997), FALZ(GenBank ID: gil38788274), GCN5L2 (GenBank ID: gil10835101), KIAA1240(GenBank ID: gil51460532), LOC93349 (GenBank ID: gil1134133279), PB1(1)(GenBank ID: gil30794372), PB1(2) (GenBank ID: gil30794372), PB1(3)(GenBank ID: gil30794372), PB1(5) (GenBank ID: gil30794372), PB1(6)(GenBank ID: gil30794372), PCAF (GenBank ID: gil40805843), PHIP(2)(GenBank ID: gil134996489), SMARC A2 (GenBank ID: gil48255900), SMARC A4(GenBank ID: gil121071056), SP140 (GenBank ID: gil152487219), TAF1(1)(GenBank ID: gil20357585), TAF1(2) (GenBank ID: gil20357585), TAF1L(1)(GenBank ID: gil24429572), TAF1L(2) (GenBank ID: gil124429572), TIF1(GenBank ID: gil14971415), TRIM28 (GenBank ID: gil5032179), or WDR9(2)(GenBank ID: gil16445436).

The term “bromodomain-containing protein” or “bromodomain protein”refers to a protein, whether wild-type or mutant, natural or synthetic,truncated or complete, or a variant thereof, that possesses the minimumamino acid sequence sufficient for a functional bromodomain capable ofmediating molecular recognition of acetyl-lysine of acetylated lysineresidues on a second protein (e.g., a histone), such as on the tails ofhistones. Bromodomain-containing proteins include, for example, fusionproteins comprising a bromodomain and an additional portion having adesired functionality (e.g., a reporter portion).

The terms “composition” and “formulation” are used interchangeably.

A “subject” to which administration is contemplated refers to a human(i.e., male or female of any age group, e.g., pediatric subject (e.g.,infant, child, or adolescent) or adult subject (e.g., young adult,middle-aged adult, or senior adult)) or non-human animal. In certainembodiments, the non-human animal is a mammal (e.g., primate (e.g.,cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g.,cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g.,commercially relevant bird, such as chicken, duck, goose, or turkey)).In certain embodiments, the non-human animal is a fish, reptile, oramphibian. The non-human animal may be a male or female at any stage ofdevelopment. The non-human animal may be a transgenic animal orgenetically engineered animal.

The terms “disease,” “disorder,” and “condition” are usedinterchangeably herein.

The term “biological sample” refers to any sample including tissuesamples (such as tissue sections and needle biopsies of a tissue); cellsamples (e.g., cytological smears (such as Pap or blood smears) orsamples of cells obtained by microdissection); samples of wholeorganisms (such as samples of yeasts or bacteria); or cell fractions,fragments or organelles (such as obtained by lysing cells and separatingthe components thereof by centrifugation or otherwise). Other examplesof biological samples include blood, serum, urine, semen, fecal matter,cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus,biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy),nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccalswabs), or any material containing biomolecules that is derived from afirst biological sample.

The term “administer,” “administering,” or “administration” refers toimplanting, absorbing, ingesting, injecting, inhaling, or otherwiseintroducing a compound described herein, or a composition thereof, in oron a subject.

The terms “condition,” “disease,” and “disorder” are usedinterchangeably.

The terms “treatment,” “treat,” and “treating” refer to reversing,alleviating, delaying the onset of, or inhibiting the progress of adisease described herein. In some embodiments, treatment may beadministered after one or more signs or symptoms of the disease havedeveloped or have been observed. In other embodiments, treatment may beadministered in the absence of signs or symptoms of the disease. Forexample, treatment may be administered to a susceptible subject prior tothe onset of symptoms (e.g., in light of a history of symptoms and/or inlight of exposure to a pathogen). Treatment may also be continued aftersymptoms have resolved, for example, to delay or prevent recurrence.

An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, i.e., treating thecondition. As will be appreciated by those of ordinary skill in thisart, the effective amount of a compound described herein may varydepending on such factors as the desired biological endpoint, thepharmacokinetics of the compound, the condition being treated, the modeof administration, and the age and health of the subject. An effectiveamount encompasses therapeutic and prophylactic treatment.

A “therapeutically effective amount” of a compound described herein isan amount sufficient to provide a therapeutic benefit in the treatmentof a condition or to delay or minimize one or more symptoms associatedwith the condition. A therapeutically effective amount of a compoundmeans an amount of therapeutic agent, alone or in combination with othertherapies, which provides a therapeutic benefit in the treatment of thecondition. The term “therapeutically effective amount” can encompass anamount that improves overall therapy, reduces or avoids symptoms, signs,or causes of the condition, and/or enhances the therapeutic efficacy ofanother therapeutic agent. In certain embodiments, a therapeuticallyeffective amount is effective for inhibiting the activity of abromodomain-containing protein. In certain embodiments, atherapeutically effective amount is effective for treating a diseasedescribed herein. In certain embodiments, a therapeutically effectiveamount is effective for inhibiting the activity of abromodomain-containing protein and for treating a disease describedherein.

A “prophylactically effective amount” of a compound described herein isan amount sufficient to prevent a condition, or one or more symptomsassociated with the condition or prevent its recurrence. Aprophylactically effective amount of a compound means an amount of atherapeutic agent, alone or in combination with other agents, whichprovides a prophylactic benefit in the prevention of the condition. Theterm “prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent. In certain embodiments, a prophylacticallyeffective amount is effective for inhibiting the activity of abromodomain-containing protein. In certain embodiments, aprophylactically effective amount is effective for preventing a diseasedescribed herein. In certain embodiments, a prophylactically effectiveamount is effective for inhibiting the activity of abromodomain-containing protein and for preventing a disease describedherein.

The term “inhibition”, “inhibiting”, “inhibit,” or “inhibitor” refer tothe ability of a compound to reduce, slow, halt or prevent activity of aparticular biological process (e.g., activity of a bromodomain and/or abromodomain-containing protein) in a cell relative to vehicle. In someembodiments, the term refers to a reduction of the level of enzymeactivity, e.g., (bromodomain, bromodomain-containing protein activity),to a level that is statistically significantly lower than an initiallevel, which may, for example, be a baseline level of enzyme activity.In some embodiments, the term refers to a reduction of the level ofenzyme activity, e.g., (bromodomain, bromodomain-containing protein)activity, to a level that is less than 75%, less than 50%, less than40%, less than 30%, less than 25%, less than 20%, less than 10%, lessthan 9%, less than 8%, less than 7%, less than 6%, less than 5%, lessthan 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, lessthan 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of aninitial level, which may, for example, be a baseline level of enzymeactivity.

When a compound, pharmaceutical composition, method, use, or kit isreferred to as “selectively,” “specifically,” or “competitively” bindinga first protein or a first chromatin, the compound, pharmaceuticalcomposition, method, use, or kit binds the first protein or the firstchromatin with a higher binding affinity (e.g., not less than about2-fold, not less than about 5-fold, not less than about 10-fold, notless than about 30-fold, not less than about 100-fold, not less thanabout 1,000-fold, or not less than about 10,000-fold) than binding asecond protein or second chromatin that is different from the firstprotein and the first chromatin. When a compound, pharmaceuticalcomposition, method, use, or kit is referred to as “selectively,”“specifically,” or “competitively” modulating (e.g., increasing orinhibiting) the activity of a bromodomain-containing protein, thecompound, pharmaceutical composition, method, use, or kit modulates theactivity of the bromodomain-containing protein to a greater extent(e.g., not less than about 2-fold, not less than about 5-fold, not lessthan about 10-fold, not less than about 30-fold, not less than about100-fold, not less than about 1,000-fold, or not less than about10,000-fold) than the activity of at least one protein that is differentfrom the bromodomain-containing protein.

The term “aberrant activity” refers to activity deviating from normalactivity. The term “increased activity” refers to activity higher thannormal activity.

A “proliferative disease” refers to a disease that occurs due toabnormal growth or extension by the multiplication of cells (Walker,Cambridge Dictionary of Biology; Cambridge University Press: Cambridge,UK, 1990). A proliferative disease may be associated with: 1) thepathological proliferation of normally quiescent cells; 2) thepathological migration of cells from their normal location (e.g.,metastasis of neoplastic cells); 3) the pathological expression ofproteolytic enzymes such as the matrix metalloproteinases (e.g.,collagenases, gelatinases, and elastases); or 4) the pathologicalangiogenesis as in proliferative retinopathy and tumor metastasis.Exemplary proliferative diseases include cancers (i.e., “malignantneoplasms”), benign neoplasms, diseases associated with angiogenesis,inflammatory diseases, and autoimmune diseases.

The term “angiogenesis” refers to the physiological process throughwhich new blood vessels form from pre-existing vessels. Angiogenesis isdistinct from vasculogenesis, which is the de novo formation ofendothelial cells from mesoderm cell precursors. The first vessels in adeveloping embryo form through vasculogenesis, after which angiogenesisis responsible for most blood vessel growth during normal or abnormaldevelopment. Angiogenesis is a vital process in growth and development,as well as in wound healing and in the formation of granulation tissue.However, angiogenesis is also a fundamental step in the transition oftumors from a benign state to a malignant one, leading to the use ofangiogenesis inhibitors in the treatment of cancer. Angiogenesis may bechemically stimulated by angiogenic proteins, such as growth factors(e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g.,excessive or insufficient) angiogenesis that amounts to and/or isassociated with a disease.

The terms “neoplasm” and “tumor” are used interchangeably and refer toan abnormal mass of tissue wherein the growth of the mass surpasses andis not coordinated with the growth of a normal tissue. A neoplasm ortumor may be “benign” or “malignant,” depending on the followingcharacteristics: degree of cellular differentiation (includingmorphology and functionality), rate of growth, local invasion, andmetastasis. A “benign neoplasm” is generally well differentiated, hascharacteristically slower growth than a malignant neoplasm, and remainslocalized to the site of origin. In addition, a benign neoplasm does nothave the capacity to infiltrate, invade, or metastasize to distantsites. Exemplary benign neoplasms include, but are not limited to,lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheickeratoses, lentigos, and sebaceous hyperplasias. In some cases, certain“benign” tumors may later give rise to malignant neoplasms, which mayresult from additional genetic changes in a subpopulation of the tumor'sneoplastic cells, and these tumors are referred to as “pre-malignantneoplasms.” An exemplary pre-malignant neoplasm is a teratoma. Incontrast, a “malignant neoplasm” is generally poorly differentiated(anaplasia) and has characteristically rapid growth accompanied byprogressive infiltration, invasion, and destruction of the surroundingtissue. Furthermore, a malignant neoplasm generally has the capacity tometastasize to distant sites. The term “metastasis,” “metastatic,” or“metastasize” refers to the spread or migration of cancerous cells froma primary or original tumor to another organ or tissue and is typicallyidentifiable by the presence of a “secondary tumor” or “secondary cellmass” of the tissue type of the primary or original tumor and not ofthat of the organ or tissue in which the secondary (metastatic) tumor islocated. For example, a prostate cancer that has migrated to bone issaid to be metastasized prostate cancer and includes cancerous prostatecancer cells growing in bone tissue. The term “cancer” refers to amalignant neoplasm (Stedman's Medical Dictionary, 25th ed.; Hensyl ed.;Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, butare not limited to, acoustic neuroma; adenocarcinoma; adrenal glandcancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma,lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benignmonoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma);bladder cancer; breast cancer (e.g., adenocarcinoma of the breast,papillary carcinoma of the breast, mammary cancer, medullary carcinomaof the breast); brain cancer (e.g., meningioma, glioblastomas, glioma(e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchuscancer; carcinoid tumor; cervical cancer (e.g., cervicaladenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma;colorectal cancer (e.g., colon cancer, rectal cancer, colorectaladenocarcinoma); connective tissue cancer; epithelial carcinoma;ependymoma; endotheliosarcoma (e.g., Kaposi's sarcoma, multipleidiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterinecancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of theesophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular cancer(e.g., intraocular melanoma, retinoblastoma); familiarhypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomachadenocarcinoma); gastrointestinal stromal tumor (GIST); germ cellcancer; head and neck cancer (e.g., head and neck squamous cellcarcinoma, oral cancer (e.g., oral squamous cell carcinoma), throatcancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngealcancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemiasuch as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL),acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronicmyelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chroniclymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphomasuch as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) andnon-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large celllymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicularlymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma(CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas(e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodalmarginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma),primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacyticlymphoma (i.e., Waldenström's macroglobulinemia), hairy cell leukemia(HCL), immunoblastic large cell lymphoma, precursor B-lymphoblasticlymphoma and primary central nervous system (CNS) lymphoma; and T-cellNHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheralT-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma,extranodal natural killer T-cell lymphoma, enteropathy type T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplasticlarge cell lymphoma); a mixture of one or more leukemia/lymphoma asdescribed above; and multiple myeloma (MM)), heavy chain disease (e.g.,alpha chain disease, gamma chain disease, mu chain disease);hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastictumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastomaa.k.a. Wilms' tumor, renal cell carcinoma); liver cancer (e.g.,hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g.,bronchogenic carcinoma, small cell lung cancer (SCLC), non-small celllung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS);mastocytosis (e.g., systemic mastocytosis); muscle cancer;myelodysplastic syndrome (MDS); mesothelioma; myeloproliferativedisorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis(ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML),chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES));neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreaticneuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarianembryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma;pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductalpapillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer(e.g., Paget's disease of the penis and scrotum); pinealoma; primitiveneuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplasticsyndromes; intraepithelial neoplasms; prostate cancer (e.g., prostateadenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer;skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA),melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g.,appendix cancer); soft tissue sarcoma (e.g., malignant fibroushistiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor(MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous glandcarcinoma; small intestine cancer; sweat gland carcinoma; synovioma;testicular cancer (e.g., seminoma, testicular embryonal carcinoma);thyroid cancer (e.g., papillary carcinoma of the thyroid, papillarythyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer;vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

The term “inflammatory disease” refers to a disease caused by, resultingfrom, or resulting in inflammation. The term “inflammatory disease” mayalso refer to a dysregulated inflammatory reaction that causes anexaggerated response by macrophages, granulocytes, and/or T-lymphocytesleading to abnormal tissue damage and/or cell death. An inflammatorydisease can be either an acute or chronic inflammatory condition and canresult from infections or non-infectious causes. Inflammatory diseasesinclude, without limitation, atherosclerosis, arteriosclerosis,autoimmune disorders, multiple sclerosis, systemic lupus erythematosus,polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis,tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis,rheumatoid arthritis, inflammatory arthritis, Sjogren's syndrome, giantcell arteritis, progressive systemic sclerosis (scleroderma), ankylosingspondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid,diabetes (e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis,Graves' disease, Goodpasture's disease, mixed connective tissue disease,sclerosing cholangitis, inflammatory bowel disease, Crohn's disease,ulcerative colitis, pernicious anemia, inflammatory dermatoses, usualinterstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis,berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamativeinterstitial pneumonia, lymphoid interstitial pneumonia, giant cellinterstitial pneumonia, cellular interstitial pneumonia, extrinsicallergic alveolitis, Wegener's granulomatosis and related forms ofangiitis (temporal arteritis and polyarteritis nodosa), inflammatorydermatoses, delayed-type hypersensitivity reactions (e.g., poison ivydermatitis), pneumonia, respiratory tract inflammation, AdultRespiratory Distress Syndrome (ARDS), encephalitis, immediatehypersensitivity reactions, asthma, hayfever, allergies, acuteanaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury),reperfusion injury, allograft rejection, host-versus-graft rejection,appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis,cervicitis, cholangitis, chorioamnionitis, conjunctivitis,dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis,enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis,gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis,myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis,pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis,urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis,vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, opticneuritis, temporal arteritis, transverse myelitis, necrotizingfasciitis, and necrotizing enterocolitis. An ocular inflammatory diseaseincludes, but is not limited to, post-surgical inflammation.

An “autoimmune disease” refers to a disease arising from aninappropriate immune response of the body of a subject againstsubstances and tissues normally present in the body. In other words, theimmune system mistakes some part of the body as a pathogen and attacksits own cells. This may be restricted to certain organs (e.g., inautoimmune thyroiditis) or involve a particular tissue in differentplaces (e.g., Goodpasture's disease which may affect the basementmembrane in both the lung and kidney). The treatment of autoimmunediseases is typically with immunosuppression, e.g., medications whichdecrease the immune response. Exemplary autoimmune diseases include, butare not limited to, glomerulonephritis, Goodpasture's syndrome,necrotizing vasculitis, lymphadenitis, peri-arteritis nodosa, systemiclupus erythematosis, rheumatoid, arthritis, psoriatic arthritis,systemic lupus erythematosis, psoriasis, ulcerative colitis, systemicsclerosis, dermatomyositis/polymyositis, anti-phospholipid antibodysyndrome, scleroderma, pemphigus vulgaris, ANCA-associated vasculitis(e.g., Wegener's granulomatosis, microscopic polyangiitis), uveitis,Sjogren's syndrome, Crohn's disease, Reiter's syndrome, ankylosingspondylitis, Lyme disease, Guillain-Barré syndrome, Hashimoto'sthyroiditis, and cardiomyopathy.

The term “neurological disease” refers to any disease of the nervoussystem, including diseases that involve the central nervous system(brain, brainstem and cerebellum), the peripheral nervous system(including cranial nerves), and the autonomic nervous system (parts ofwhich are located in both central and peripheral nervous system).Neurodegenerative diseases refer to a type of neurological diseasemarked by the loss of nerve cells, including, but not limited to,Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis,tauopathies (including frontotemporal dementia), and Huntington'sdisease. Examples of neurological diseases include, but are not limitedto, headache, stupor and coma, dementia, seizure, sleep disorders,trauma, infections, neoplasms, neuro-ophthalmology, movement disorders,demyelinating diseases, spinal cord disorders, and disorders ofperipheral nerves, muscle and neuromuscular junctions. Addiction andmental illness, include, but are not limited to, bipolar disorder andschizophrenia, are also included in the definition of neurologicaldiseases. Further examples of neurological diseases include acquiredepileptiform aphasia; acute disseminated encephalomyelitis;adrenoleukodystrophy; agenesis of the corpus callosum; agnosia; Aicardisyndrome; Alexander disease; Alpers' disease; alternating hemiplegia;Alzheimer's disease; amyotrophic lateral sclerosis; anencephaly;Angelman syndrome; angiomatosis; anoxia; aphasia; apraxia; arachnoidcysts; arachnoiditis; Arnold-Chiari malformation; arteriovenousmalformation; Asperger syndrome; ataxia telangiectasia; attentiondeficit hyperactivity disorder; autism; autonomic dysfunction; backpain; Batten disease; Behcet's disease; Bell's palsy; benign essentialblepharospasm; benign focal; amyotrophy; benign intracranialhypertension; Binswanger's disease; blepharospasm; Bloch Sulzbergersyndrome; brachial plexus injury; brain abscess; bbrain injury; braintumors (including glioblastoma multiforme); spinal tumor; Brown-Sequardsyndrome; Canavan disease; carpal tunnel syndrome (CTS); causalgia;central pain syndrome; central pontine myelinolysis; cephalic disorder;cerebral aneurysm; cerebral arteriosclerosis; cerebral atrophy; cerebralgigantism; cerebral palsy; Charcot-Marie-Tooth disease;chemotherapy-induced neuropathy and neuropathic pain; Chiarimalformation; chorea; chronic inflammatory demyelinating polyneuropathy(CIDP); chronic pain; chronic regional pain syndrome; Coffin Lowrysyndrome; coma, including persistent vegetative state; congenital facialdiplegia; corticobasal degeneration; cranial arteritis;craniosynostosis; Creutzfeldt-Jakob disease; cumulative traumadisorders; Cushing's syndrome; cytomegalic inclusion body disease(CIBD); cytomegalovirus infection; dancing eyes-dancing feet syndrome;Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome;Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic neuropathy;diffuse sclerosis; dysautonomia; dysgraphia; dyslexia; dystonias; earlyinfantile epileptic encephalopathy; empty sella syndrome; encephalitis;encephaloceles; encephalotrigeminal angiomatosis; epilepsy; Erb's palsy;essential tremor; Fabry's disease; Fahr's syndrome; fainting; familialspastic paralysis; febrile seizures; Fisher syndrome; Friedreich'sataxia; frontotemporal dementia and other “tauopathies”; Gaucher'sdisease; Gerstmann's syndrome; giant cell arteritis; giant cellinclusion disease; globoid cell leukodystrophy; Guillain-Barre syndrome;HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head injury;headache; hemifacial spasm; hereditary spastic paraplegia; heredopathiaatactica polyneuritiformis; herpes zoster oticus; herpes zoster;Hirayama syndrome; HIV-associated dementia and neuropathy (see alsoneurological manifestations of AIDS); holoprosencephaly; Huntington'sdisease and other polyglutamine repeat diseases; hydranencephaly;hydrocephalus; hypercortisolism; hypoxia; immune-mediatedencephalomyelitis; inclusion body myositis; incontinentia pigmenti;infantile; phytanic acid storage disease; Infantile Refsum disease;infantile spasms; inflammatory myopathy; intracranial cyst; intracranialhypertension; Joubert syndrome; Kearns-Sayre syndrome; Kennedy disease;Kinsbourne syndrome; Klippel Feil syndrome; Krabbe disease;Kugelberg-Welander disease; kuru; Lafora disease; Lambert-Eatonmyasthenic syndrome; Landau-Kleffner syndrome; lateral medullary(Wallenberg) syndrome; learning disabilities; Leigh's disease;Lennox-Gastaut syndrome; Lesch-Nyhan syndrome; leukodystrophy; Lewy bodydementia; lissencephaly; locked-in syndrome; Lou Gehrig's disease (akamotor neuron disease or amyotrophic lateral sclerosis); lumbar discdisease; lyme disease-neurological sequelae; Machado-Joseph disease;macrencephaly; megalencephaly; Melkersson-Rosenthal syndrome; Menieresdisease; meningitis; Menkes disease; metachromatic leukodystrophy;microcephaly; migraine; Miller Fisher syndrome; mini-strokes;mitochondrial myopathies; Mobius syndrome; monomelic amyotrophy; motorneurone disease; moyamoya disease; mucopolysaccharidoses; multi-infarctdementia; multifocal motor neuropathy; multiple sclerosis and otherdemyelinating disorders; multiple system atrophy with posturalhypotension; muscular dystrophy; myasthenia gravis; myelinoclasticdiffuse sclerosis; myoclonic encephalopathy of infants; myoclonus;myopathy; myotonia congenital; narcolepsy; neurofibromatosis;neuroleptic malignant syndrome; neurological manifestations of AIDS;neurological sequelae of lupus; neuromyotonia; neuronal ceroidlipofuscinosis; neuronal migration disorders; Niemann-Pick disease;O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinaldysraphism sequence; Ohtahara syndrome; olivopontocerebellar atrophy;opsoclonus myoclonus; optic neuritis; orthostatic hypotension; overusesyndrome; paresthesia; Parkinson's disease; paramyotonia congenita;paraneoplastic diseases; paroxysmal attacks; Parry Romberg syndrome;Pelizaeus-Merzbacher disease; periodic paralyses; peripheral neuropathy;painful neuropathy and neuropathic pain; persistent vegetative state;pervasive developmental disorders; photic sneeze reflex; phytanic acidstorage disease; Pick's disease; pinched nerve; pituitary tumors;polymyositis; porencephaly; Post-Polio syndrome; postherpetic neuralgia(PHN); postinfectious encephalomyelitis; postural hypotension;Prader-Willi syndrome; primary lateral sclerosis; prion diseases;progressive; hemifacial atrophy; progressive multifocalleukoencephalopathy; progressive sclerosing poliodystrophy; progressivesupranuclear palsy; pseudotumor cerebri; Ramsay-Hunt syndrome (Type Iand Type II); Rasmussen's Encephalitis; reflex sympathetic dystrophysyndrome; Refsum disease; repetitive motion disorders; repetitive stressinjuries; restless legs syndrome; retrovirus-associated myelopathy; Rettsyndrome; Reye's syndrome; Saint Vitus Dance; Sandhoff disease;Schilder's disease; schizencephaly; septo-optic dysplasia; shaken babysyndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome; sleepapnea; Soto's syndrome; spasticity; spina bifida; spinal cord injury;spinal cord tumors; spinal muscular atrophy; stiff-person syndrome;stroke; Sturge-Weber syndrome; subacute sclerosing panencephalitis;subarachnoid hemorrhage; subcortical arteriosclerotic encephalopathy;sydenham chorea; syncope; syringomyelia; tardive dyskinesia; Tay-Sachsdisease; temporal arteritis; tethered spinal cord syndrome; Thomsendisease; thoracic outlet syndrome; tic douloureux; Todd's paralysis;Tourette syndrome; transient ischemic attack; transmissible spongiformencephalopathies; transverse myelitis; traumatic brain injury; tremor;trigeminal neuralgia; tropical spastic paraparesis; tuberous sclerosis;vascular dementia (multi-infarct dementia); vasculitis includingtemporal arteritis; Von Hippel-Lindau Disease (VHL); Wallenberg'ssyndrome; Werdnig-Hoffman disease; West syndrome; whiplash; Williamssyndrome; Wilson's disease; and Zellweger syndrome.

The term “metabolic disorder” refers to any disorder that involves analteration in the normal metabolism of carbohydrates, lipids, proteins,nucleic acids, or a combination thereof. A metabolic disorder isassociated with either a deficiency or excess in a metabolic pathwayresulting in an imbalance in metabolism of nucleic acids, proteins,lipids, and/or carbohydrates. Factors affecting metabolism include, andare not limited to, the endocrine (hormonal) control system (e.g., theinsulin pathway, the enteroendocrine hormones including GLP-1, PYY orthe like), the neural control system (e.g., GLP-1 in the brain), or thelike. Examples of metabolic disorders include, but are not limited to,diabetes (e.g., Type I diabetes, Type II diabetes, gestationaldiabetes), hyperglycemia, hyperinsulinemia, insulin resistance, andobesity.

A “kinase” is a type of enzyme that transfers phosphate groups from highenergy donor molecules, such as ATP, to specific substrates, referred toas phosphorylation. Kinases are part of the larger family ofphosphotransferases. One of the largest groups of kinases are proteinkinases, which act on and modify the activity of specific proteins.Kinases are used extensively to transmit signals and control complexprocesses in cells. Various other kinases act on small molecules such aslipids, carbohydrates, amino acids, and nucleotides, either forsignaling or to prime them for metabolic pathways. Kinases are oftennamed after their substrates. More than 500 different protein kinaseshave been identified in humans. These exemplary human protein kinasesinclude, but are not limited to, AAK1, ABL, ACK, ACTR2, ACTR2B, AKT1,AKT2, AKT3, ALK, ALK1, ALK2, ALK4, ALK7, AMPKa1, AMPKa2, ANKRD3, ANPa,ANPb, ARAF, ARAFps, ARG, AurA, AurAps1, AurAps2, AurB, AurBps1, AurC,AXL, BARK1, BARK2, BIKE, BLK, BMPR1A, BMPR1Aps1, BMPR1Aps2, BMPR1B,BMPR2, BMX, BRAF, BRAFps, BRK, BRSK1, BRSK2, BTK, BUB1, BUBR1, CaMK1a,CaMK1b, CaMK1d, CaMK1g, CaMK2a, CaMK2b, CaMK2d, CaMK2g, CaMK4, CaMKK1,CaMKK2, caMLCK, CASK, CCK4, CCRK, CDCl₂, CDCl₇, CDK10, CDK11, CDK2,CDK3, CDK4, CDK4ps, CDK5, CDK5ps, CDK6, CDK7, CDK7ps, CDK8, CDK8ps,CDK9, CDKL1, CDKL2, CDKL3, CDKL4, CDKL5, CGDps, CHED, CHK1, CHK2,CHK2ps1, CHK2ps2, CK1a, CK1a2, CK1aps1, CK1aps2, CK1aps3, CK1d, CK1e,CK1g1, CK1g2, CK1g2ps, CK1g3, CK2a1, CK2a1-rs, CK2a2, CLIK1, CLIK1L,CLK1, CLK2, CLK2ps, CLK3, CLK3ps, CLK4, COT, CRIK, CRK7, CSK, CTK, CYGD,CYGF, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK,DMPK1, DMPK2, DRAK1, DRAK2, DYRKIA, DYRK1B, DYRK2, DYRK3, DYRK4, EGFR,EphA1, EphA10, EphA2, EphA3, EphA4, EphA5, EphA6, EphA7, EphA8, EphB1,EphB2, EphB3, EphB4, EphB6, Erk1, Erk2, Erk3, Erk3ps1, Erk3ps2, Erk3ps3,Erk3ps4, Erk4, Erk5, Erk7, FAK, FER, FERps, FES, FGFR1, FGFR2, FGFR3,FGFR4, FGR, FLT1, FLT1ps, FLT3, FLT4, FMS, FRK, Fused, FYN, GAK, GCK,GCN2, GCN22, GPRK4, GPRK5, GPRK6, GPRK6ps, GPRK7, GSK3A, GSK3B, Haspin,HCK, HER2/ErbB2, HER3/ErbB3, HER4/ErbB4, HH498, HIPK1, HIPK2, HIPK3,HIPK4, HPK1, HRI, HRIps, HSER, HUNK, ICK, IGF1R, IKKa, IKKb, IKKe, ILK,INSR, IRAK1, IRAK2, IRAK3, IRAK4, IRE1, IRE2, IRR, ITK, JAK1, JAK12,JAK2, JAK22, JAK3, JAK32, JNK1, JNK2, JNK3, KDR, KHS1, KHS2, KIS, KIT,KSGCps, KSR1, KSR2, LATS1, LATS2, LCK, LIMK1, LIMK2, LIMK2ps, LKB1,LMR1, LMR2, LMR3, LOK, LRRK1, LRRK2, LTK, LYN, LZK, MAK, MAP2K1,MAP2K1ps, MAP2K2, MAP2K2ps, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7,MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8,MAPKAPK2, MAPKAPK3, MAPKAPK5, MAPKAPKps1, MARK1, MARK2, MARK3, MARK4,MARKps01, MARKps02, MARKps03, MARKps04, MARKps05, MARKps07, MARKps08,MARKps09, MARKps10, MARKps11, MARKps12, MARKps13, MARKps15, MARKps16,MARKps17, MARKps18, MARKps19, MARKps20, MARKps21, MARKps22, MARKps23,MARKps24, MARKps25, MARKps26, MARKps27, MARKps28, MARKps29, MARKps30,MAST1, MAST2, MAST3, MAST4, MASTL, MELK, MER, MET, MISR2, MLK1, MLK2,MLK3, MLK4, MLKL, MNK1, MNK1ps, MNK2, MOK, MOS, MPSK1, MPSK1ps, MRCKa,MRCKb, MRCKps, MSK1, MSK12, MSK2, MSK22, MSSK1, MST1, MST2, MST3,MST3ps, MST4, MUSK, MYO3A, MYO3B, MYT1, NDR1, NDR2, NEK1, NEK10, NEK11,NEK2, NEK2ps1, NEK2ps2, NEK2ps3, NEK3, NEK4, NEK4ps, NEK5, NEK6, NEK7,NEK8, NEK9, NIK, NIM1, NLK, NRBP1, NRBP2, NuaK1, NuaK2, Obsen, Obscn2,OSR1, p38a, p38b, p38d, p38g, p70S6K, p70S6Kb, p70S6Kps1, p70S6Kps2,PAK1, PAK2, PAK2ps, PAK3, PAK4, PAK5, PAK6, PASK, PBK, PCTAIRE1,PCTAIRE2, PCTAIRE3, PDGFRa, PDGFRb, PDK1, PEK, PFTAIRE1, PFTAIRE2,PHKg1, PHKg1ps1, PHKg1ps2, PHKg1ps3, PHKg2, PIK3R4, PIM1, PIM2, PIM3,PINK1, PITSLRE, PKACa, PKACb, PKACg, PKCa, PKCb, PKCd, PKCe, PKCg, PKCh,PKCi, PKCips, PKCt, PKCz, PKD1, PKD2, PKD3, PKG1, PKG2, PKN1, PKN2,PKN3, PKR, PLK1, PLK1ps1, PLK1ps2, PLK2, PLK3, PLK4, PRKX, PRKXps, PRKY,PRP4, PRP4ps, PRPK, PSKH1, PSKH1ps, PSKH2, PYK2, QIK, QSK, RAF1, RAF1ps,RET, RHOK, RIPK1, RIPK2, RIPK3, RNAseL, ROCK1, ROCK2, RON, ROR1, ROR2,ROS, RSK1, RSK12, RSK2, RSK22, RSK3, RSK32, RSK4, RSK42, RSKL1, RSKL2,RYK, RYKps, SAKps, SBK, SCYL1, SCYL2, SCYL2ps, SCYL3, SGK, SgK050ps,SgK069, SgK071, SgK085, SgK110, SgK196, SGK2, SgK223, SgK269, SgK288,SGK3, SgK307, SgK384ps, SgK396, SgK424, SgK493, SgK494, SgK495, SgK496,SIK, skMLCK, SLK, Slob, smMLCK, SNRK, SPEG, SPEG2, SRC, SRM, SRPK1,SRPK2, SRPK2ps, SSTK, STK33, STK33ps, STLK3, STLK5, STLK6, STLK6ps1,STLK6-rs, SuRTK106, SYK, TAK1, TAO1, TAO2, TAO3, TBCK, TBK1, TEC, TESK1,TESK2, TGFbR1, TGFbR2, TIE1, TIE2, TLK1, TLK1ps, TLK2, TLK2ps1, TLK2ps2,TNK1, Trad, Trb1, Trb2, Trb3, Trio, TRKA, TRKB, TRKC, TSSK1, TSSK2,TSSK3, TSSK4, TSSKps1, TSSKps2, TTBK1, TTBK2, TTK, TTN, TXK, TYK2,TYK22, TYRO3, TYRO3ps, ULK1, ULK2, ULK3, ULK4, VACAMKL, VRK1, VRK2,VRK3, VRK3ps, Wee1, Wee1B, Wee1Bps, Wee1ps1, Wee1ps2, Wnk1, Wnk2, Wnk3,Wnk4, YANK1, YANK2, YANK3, YES, YESps, YSK1, ZAK, ZAP70, ZC1/HGK,ZC2/TNIK, ZC3/MINK, ZC4/NRK.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which constitute a part of thisspecification, illustrate several embodiments of the invention andtogether with the description, serve to explain the principles of theinvention.

FIGS. 1A and 1B. Mean whole blood concentration-time profiles forcompounds 501 (FIG. 1A) and 502 (FIG. 1B) after intravenous dose at 5mg/kg or oral dose at 10 mg/kg (N=3) in male CD1 mice.

FIGS. 2A and 2B. Mean whole blood concentration-time profiles forcompounds 601, 602, 603, 604, and 605 after intravenous dose at 1 mg/kg(FIG. 2A) or oral dose at 5 mg/kg (FIG. 2B) in male CD1 mice.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

The present disclosure provides compounds of Formula (I), which bindbromodomains and/or bromodomain-containing proteins. The compoundsdescribed herein may be able to bind in a pocket of a bromodomain (e.g.,a bromodomain of a bromodomain-containing protein). In certainembodiments, the compounds described herein may bind in the pocket of abromodomain and disrupt the interaction between the bromodomain bindingpocket and an acetylated lysine residue of a second protein (e.g., ahistone). In certain embodiments, the compounds described herein bind inthe pocket of the bromodomain. The compound described herein may alsomodulate (e.g., inhibit) the activity of a bromodomain and/orbromodomain-containing protein. Also provided in the present disclosureare pharmaceutical compositions, methods, uses, and kits useful inmodulating (e.g., inhibiting) the activity of a bromodomain-containingprotein (e.g., a transcription factor). The compounds, pharmaceuticalcompositions, methods, uses, and kits may be useful in treating and/orpreventing diseases associated with a bromodomain, diseases associatedwith a bromodomain-containing protein, diseases associated with theactivity (e.g., aberrant activity) of a bromodomain, and diseasesassociated with the activity (e.g., aberrant activity) of abromodomain-containing protein. Exemplary diseases that maybe preventedand/or treated with compounds described herein include proliferativediseases (e.g., cancers, benign neoplasms, pathological angiogenesis,inflammatory diseases, and autoimmune diseases), autoimmune diseases,cardiovascular diseases, viral infections, fibrotic diseases,neurological diseases, metabolic diseases, endocrine diseases, andradiation poisoning. The compounds, pharmaceutical compositions,methods, uses, and kits may also be useful for male contraception andfor preventing and/or treating a viral infection (e.g., by inhibitingthe replication of a virus, by killing a virus).

Compounds described herein (e.g., compounds of Formula (I)) have beenfound to bind bromodomain-containing proteins. In certain embodiments,the compounds described herein bind to a bromodomain-containing protein.Without wishing to be bound by any particular theory, the compoundsdescribed herein are thought to bind in a pocket of a bromodomain of abromodomain-containing protein. In certain embodiments, the compoundsdescribed herein bind in the binding pocket of the bromodomain bymimicking the contact between an acetyl-lysine residue of a secondprotein (e.g., a histone) and the binding pocket. In certainembodiments, the compounds described herein bind in the binding pocketof the bromodomain. In certain embodiments, the compounds describedherein covalently bind to the bromodomain-containing protein. In certainembodiments, the compounds described herein non-covalently bind to thebromodomain-containing protein. In certain embodiments, the compoundsdescribed herein reversibly bind to the bromodomain-containing protein.In certain embodiments, the compounds described herein non-reversiblybind to the bromodomain-containing protein. In certain embodiments, thecompounds described herein inhibit the activity (e.g., aberrantactivity, increased activity) of a bromodomain-containing protein. Incertain embodiments, the compounds described herein inhibit the activity(e.g., aberrant activity, increased activity) of a bromodomain. Incertain embodiments, the activity of a bromodomain is the ability of thebromodomain to bind an acetylated lysine residue (e.g., an acetylatedlysine residue on the N-terminal tails of histones), which may be partof another protein or peptide. In certain embodiments, the compoundsdescribed herein specifically bind to a bromodomain-containing protein(e.g., bind to a bromodomain-containing protein with a higher bindingaffinity than to a different bromodomain-containing protein and/or to aprotein that is not a bromodomain-containing protein). In certainembodiments, the compounds described herein specifically bind to abromodomain of a bromodomain-containing protein (e.g., bind to abromodomain of a bromodomain-containing protein with a higher bindingaffinity than to a non-bromodomain of the bromodomain-containingprotein). In certain embodiments, the compounds described hereinnon-specifically bind to a bromodomain-containing protein (e.g., bind toa bromodomain of the bromodomain-containing protein). In certainembodiments, the compounds described herein reduce transcriptionalelongation. In certain embodiments, the compounds described hereindisrupt the subcellular localization of a bromodomain-containingprotein. In certain embodiments, the compounds described herein reducechromatin binding. In certain embodiments, the compounds describedherein inhibit the formation of a chromatin by reducing the binding of aprotein (e.g., histone) to a DNA. In certain embodiments, the compoundsdescribed herein inhibit the binding of Histone H4 Kac peptide to abromodomain of a bromodomain-containing protein. In certain embodiments,the compounds described herein form one or more hydrogen bonds with anevolutionarily conserved asparagine in a bromodomain of abromodomain-containing protein. In certain embodiments, the asparagineis Asn140 in BRD4(1) and Asn429 in BRD2(2). In certain embodiments, thebromodomain-containing protein is BRD4 or BRD2; and the asparagine isAsn140 in BRD4(1) and Asn429 in BRD2(2). In certain embodiments, thecompounds described herein bind competitively with chromatin in acellular environment. It is thus expected that the compounds describedherein may be useful in the treatment of a disease associated with theactivity a bromodomain-containing protein (e.g., a proliferativedisease).

The compounds described herein may bind bromodomain-containing proteinsand may inhibit the activity of the bromodomain-containing proteins. Incertain embodiments, the bromodomain-containing protein is a bromo andextra terminal (BET) protein. In certain embodiments, thebromodomain-containing protein is BRD2. In certain embodiments, thebromodomain-containing protein is BRD2(1). In certain embodiments, thebromodomain-containing protein is BRD2(2). In certain embodiments, thebromodomain-containing protein is BRD3. In certain embodiments, thebromodomain-containing protein is BRD3(1). In certain embodiments, thebromodomain-containing protein is BRD3(2). In certain embodiments, thebromodomain-containing protein is BRD4. In certain embodiments, thebromodomain-containing protein is BRD4(1). In certain embodiments, thebromodomain-containing protein is BRD4(2). In certain embodiments, thebromodomain-containing protein is BRDT. In certain embodiments, thebromodomain-containing protein is BRDT(1). In certain embodiments, thebromodomain-containing protein is BRDT(2). In certain embodiments, thebromodomain-containing protein is a TBP (TATA box bindingprotein)-associated factor protein (TAF). In certain embodiments, thebromodomain-containing protein is TAF. In certain embodiments, thebromodomain-containing protein is TAFL. In certain embodiments, thebromodomain-containing protein is CREB-binding protein (CBP). In certainembodiments, the bromodomain-containing protein is E1A binding proteinp300 (EP300).

The binding affinity of a compound described herein to abromodomain-containing protein may be measured by the dissociationconstant (K_(d)) value of an adduct of the compound described herein andthe bromodomain-containing protein using methods known in the art (e.g.,isothermal titration calorimetry (ITC)). In certain embodiments, theadduct comprises the compound described herein and thebromodomain-containing protein, which are bound (e.g., covalently ornon-covalently) to each other. In certain embodiments, the K_(d) valueof the adduct is at most about 100 μM, at most about 30 μM, at mostabout 10 μM, at most about 3 μM, at most about 1 μM, at most about 300nM, at most about 100 nM, at most about 30 nM, at most about 10 nM, atmost about 3 nM, or at most about 1 nM. In certain embodiments, theK_(d) value of the adduct is at least about 1 nM, at least about 10 nM,at least about 100 nM, at least about 1 μM, at least about 10 μM, or atleast about 100 μM. Combinations of the above-referenced ranges (e.g.,at most about 10 μM and at least about 1 nM) are also within the scopeof the disclosure. Other ranges are also possible. In certainembodiments, the K_(d) value of the adduct is at most about 10 μM. Incertain embodiments, the K_(d) value of the adduct is at most about 300nM. In certain embodiments, the K_(d) value of the adduct is at mostabout 100 nM.

In certain embodiments, the activity of the bromodomain-containingproteins described herein is inhibited by the compounds describedherein. The inhibition of the activity of a bromodomain-containingprotein by a compound described herein may be measured by the halfmaximal inhibitory concentration (IC₅₀) value of a compound describedherein when the compound described herein, or a pharmaceuticalcomposition thereof, is contacted with the bromodomain-containingprotein. In certain embodiments, IC₅₀ values are obtained by acompetition binding assay. In certain embodiments, IC₅₀ values areobtained by a method described herein. In certain embodiments, the IC₅₀value of a compound described herein is at most about 1 mM, at mostabout 300 μM, at most about 100 μM, at most about 30 M, at most about 10μM, at most about 3 μM, at most about 1 μM, at most about 300 nM, atμmost about 100 nM, at most about 30 nM, at most about 10 nM, at mostabout 3 nM, or at most about 1 nM. In certain embodiments, the IC₅₀value of a compound described herein is at least about 1 nM, at leastabout 3 nM, at least about 10 nM, at least about 30 nM, at least about100 nM, at least about 300 nM, at least about 1 μM, at least about 3 μM,at least about 10 μM, at least about 30 μM, at least about 100 μM, atleast about 300 μM, or at least 1 mM. Combinations of theabove-referenced ranges (e.g., at most about 300 μM and at least about 1M) are also within the scope of the disclosure. Other ranges are alsopossible. In certain embodiments, the IC₅₀ value of a compound describedherein is at most about 300 μM. In certain embodiments, the IC₅₀ valueof a compound described herein is at most about 30 μM. In certainembodiments, the IC₅₀ value of a compound described herein is at mostabout 10 M.

The compounds described herein may selectively inhibit the activity of abromodomain-containing protein. In certain embodiments, the compoundsdescribed herein selectively inhibit the activity of abromodomain-containing protein compared to a differentbromodomain-containing protein. In certain embodiments, the compoundsdescribed herein selectively inhibit the activity of abromodomain-containing protein compared to a protein that is not abromodomain-containing protein. In certain embodiments, the compoundsdescribed herein selectively inhibit the activity of abromodomain-containing protein compared to a kinase (e.g., a kinasedescribed herein). In certain embodiments, the compounds describedherein selectively inhibit the activity of a bromodomain-containingprotein compared to MPS1 (TTK), ERK5 (BMK1, MAPK7), a polo kinase (e.g.,polo kinase 1, polo kinase 2, polo kinase 3, polo kinase 4), Ack1, Ack2,AbI, DCAMKL1, ABL1, an AbI mutant, DCAMKL2, ARK5, BRK, MKNK2, FGFR4,TNK1, PLK1, ULK2, PLK4, PRKD1, PRKD2, PRKD3, ROS 1, RPS6KA6, TAOK1,TAOK3, TNK2, Bcr-Abl, GAK, cSrc, TPR-Met, Tie2, MET, FGFR3, Aurora, AxI,Bmx, BTK, c-kit, CHK2, Flt3, MST2, p70S6K, PDGFR, PKB, PKC, Raf, ROCK-H,Rsk1, SGK, TrkA, TrkB, and/or TrkC. In certain embodiments, thecompounds described herein selectively inhibit the activity of abromodomain-containing protein compared to a MAP kinase. In certainembodiments, the compounds described herein selectively inhibit theactivity of a bromodomain-containing protein compared to a mitoticspindle kinase. In certain embodiments, the compounds described hereinselectively inhibit the activity of a bromodomain-containing proteincompared to a polo kinase. In certain embodiments, the compoundsdescribed herein selectively inhibit a BET protein. In certainembodiments, the compounds described herein selectively inhibit BRD2. Incertain embodiments, the compounds described herein selectively inhibitBRD3. In certain embodiments, the compounds described herein selectivelyinhibit BRD4. In certain embodiments, the compounds described hereinselectively inhibit BRDT. In certain embodiments, the compoundsdescribed herein selectively inhibit a TAF protein (e.g., TAF or TAFL),CBP, and/or EP300. In certain embodiments, a compound described hereinis a non-selective inhibitor of two or more bromodomain-containingproteins. In certain embodiments, a compound described herein is anon-selective inhibitor of a bromodomain-containing protein and aprotein that is not a bromodomain-containing protein.

The selectivity of a compound described herein in inhibiting theactivity of a bromodomain-containing protein over a second protein(e.g., a kinase) that is different from the bromodomain-containingprotein may be measured by the quotient of the IC₅₀ value of thecompound described herein in inhibiting the activity of the secondprotein over the IC₅₀ value of the compound described herein ininhibiting the activity of the bromodomain-containing protein. Theselectivity of a compound described herein for a bromodomain-containingprotein over a second protein may also be measured by the quotient ofthe K_(d) value of an adduct of the compound described herein and thesecond protein over the K_(d) value of an adduct of the compounddescribed herein and the bromodomain-containing protein. In certainembodiments, the selectivity is at least about 1-fold, at least about3-fold, at least about 5-fold, at least about 10-fold, at least about30-fold, at least about 100-fold, at least about 300-fold, at leastabout 1,000-fold, at least about 3,000-fold, at least about 10,000-fold,at least about 30,000-fold, or at least about 100,000-fold. In certainembodiments, the selectivity is at most about 100,000-fold, at mostabout 10,000-fold, at most about 1,000-fold, at most about 100-fold, atmost about 10-fold, or at most about 1-fold. Combinations of theabove-referenced ranges (e.g., at least about 2-fold and at most about10,000-fold) are also within the scope of the disclosure. Other rangesare also possible. In certain embodiments, the selectivity is at leastabout 3-fold. In certain embodiments, the selectivity is at least about10-fold. In certain embodiments, the selectivity is at least about50-fold. In certain embodiments, the selectivity is at least about100-fold. In certain embodiments, the selectivity is at least about1,000-fold.

It is known in the art that a bromodomain-containing protein isimplicated in a wide range of diseases. For example, BRD3 and BRD4 arerelated to BRD3 NUT midline carcinoma and BRD4 NUT midline carcinoma,respectively. BRDT is related to sperm formation, and CBP is related tomixed-lineage leukemia (MLL). Therefore, the compounds described hereinare expected to be useful in treating and/or preventing diseasesassociated with bromodomain-containing proteins or as a malecontraceptive.

Compounds of Formula (I)

In one aspect, the present invention provides compounds of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof, wherein:

-   -   Y is of formula:

-   -   wherein:        -   R⁴ hydrogen, optionally substituted alkyl, optionally            substituted acyl, or a nitrogen protecting group;        -   L¹ is optionally substituted alkylene;        -   L⁴ is unsubstituted branched alkylene or substituted            alkylene;        -   X⁴ is halogen, —OR^(f), —SR^(f), or —N(R^(f))₂;        -   Ring D is a carbocyclic or a heterocyclic ring, wherein the            heterocyclic ring contains one heteroatom, and the            heteroatom is N;        -   Ring G is a bicyclic heterocyclic or bicyclic heteroaryl            ring, wherein the rings share exactly two atoms;        -   E is —O—, —S—, —N(R^(E))—, or —CH(R^(E))—, wherein R^(E) is            optionally substituted carbocyclyl, optionally substituted            heterocyclyl, optionally substituted aryl, or optionally            substituted heteroaryl;        -   each occurrence of R^(D) is independently hydrogen, halogen,            optionally substituted alkyl, optionally substituted            heteroalkyl, optionally substituted alkenyl, optionally            substituted alkynyl, optionally substituted carbocyclyl,            optionally substituted heterocyclyl, optionally substituted            aryl, optionally substituted heteroaryl, optionally            substituted acyl, —OR^(f), —SR^(f), —N(R^(f))₂, —NO₂, or            —CN, or two R^(D) attached to adjacent atoms are joined to            form an optionally substituted carbocyclyl, optionally            substituted heterocyclyl, optionally substituted aryl,            optionally substituted heteroaryl ring;        -   z is 0, 1, or 2; and        -   d is 0, 1, 2, 3, or 4;    -   R^(A1) is hydrogen, halogen, optionally substituted alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted carbocyclyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted acyl, —OR^(f),        —SR^(f), —N(R^(f))₂, —NO₂, or —CN;    -   R^(A2) is hydrogen, halogen, optionally substituted alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted carbocyclyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted acyl, —OR^(f),        —SR^(f), —N(R^(f))₂, —NO₂, or —CN;    -   X¹ is N or CR⁵, wherein R⁵ is hydrogen, halogen, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted carbocyclyl,        optionally substituted heterocyclyl, optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        acyl, —OR^(f), —SR^(f), —N(R^(f))₂, —NO₂, or —CN;    -   R^(B) is hydrogen, halogen, optionally substituted alkyl,        optionally substituted alkenyl, optionally substituted alkynyl,        optionally substituted carbocyclyl, optionally substituted        heterocyclyl, optionally substituted aryl, optionally        substituted heteroaryl, optionally substituted acyl, —OR^(f),        —SR^(f), —N(R^(f))₂, —NO₂, or —CN;    -   Ring C is aryl or heteroaryl;    -   each occurrence of R^(C) is independently halogen, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted carbocyclyl,        optionally substituted heterocyclyl, optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        acyl, optionally substituted sulfonyl, —OR^(f), —SR^(f),        —N(R^(f))₂, —NO₂, or —CN;    -   c is 0, 1, 2, 3, or 4;    -   n is 0, 1, 2, 3, or 4;    -   R² is hydrogen, halogen, or optionally substituted alkyl; and    -   each occurrence of R^(f) is independently hydrogen, optionally        substituted alkyl, optionally substituted alkenyl, optionally        substituted alkynyl, optionally substituted carbocyclyl,        optionally substituted heterocyclyl, optionally substituted        aryl, optionally substituted heteroaryl, optionally substituted        acyl, optionally substituted sulfonyl, an oxygen protecting        group, or a nitrogen protecting group, or two R^(f) are joined        to form an optionally substituted heterocyclic or optionally        substituted heteroaryl ring.

In certain embodiments Y is of formula:

In certain embodiments, compounds of Formula (I) do not includecompounds disclosed in any of U.S. Pat. Nos. 5,712,274, 8,044,042,8,476,260, 8,981,083, WIPO Application No. PCT/US2014/023386, filed Mar.11, 2014, WIPO Application No. PCT/US2011/036647, filed May 16, 2011,WIPO Application No. PCT/US2011/036667, filed May 16, 2011, WIPOApplication No. PCT/US2011/036672, filed May 16, 2011, WIPO ApplicationNo. PCT/US2011/036701, filed May 16, 2011, WIPO Application No.PCT/JP2008/073864, filed Dec. 26, 2008, WIPO Application No.PCT/JP1992/001198, Sep. 18, 1992, WIPO Application No.PCT/JP1993/001329, filed Sep. 16, 1993, and WIPO Application No.PCT/JP2006/310709, filed May 30, 2006.

As generally defined herein, n is 0, 1, 2, 3, or 4. In certainembodiments, n is 0. In certain embodiments, n is 1. In certainembodiments, n is 2. In certain embodiments, n is 3. In certainembodiments, n is 4. In certain embodiments, n is 0, 1, 2, or 3. Incertain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0or 1. In certain embodiments, n is 1, 2, 3, or 4. In certainembodiments, n is 2, 3, or 4. In certain embodiments, n is 3 or 4. Incertain embodiments, n is 0, 2, 3, or 4.

Group Y

As generally defined herein, Y is of formula:

As generally defined herein R⁴ is hydrogen, optionally substitutedalkyl, optionally substituted acyl, or a nitrogen protecting group. Incertain embodiments, R⁴ is hydrogen.

In certain embodiments, R⁴ is optionally substituted alkyl, e.g.,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₂ alkyl,optionally substituted C₂₋₃ alkyl, optionally substituted C₃₋₄ alkyl,optionally substituted C₄₋₅ alkyl, or optionally substituted C₅₋₆ alkyl.In certain embodiments, R⁴ is unsubstituted alkyl, e.g., unsubstitutedC₁₋₆ alkyl, unsubstituted C₁₋₂ alkyl, unsubstituted C₂₋₃ alkyl,unsubstituted C₃₋₄ alkyl, unsubstituted C₄₋₅ alkyl, or unsubstitutedC₅₋₆ alkyl. In certain embodiments, R⁴ is methyl. In certainembodiments, R⁴ is ethyl, propyl, or butyl. In certain embodiments, R⁴is haloalkyl, e.g., —CHF₂, —CHC₂, —CH₂CHF₂, —CH₂CHCl₂. In certainembodiments, R⁴ is perhaloalkyl, e.g., —CF₃, —CF₂CF₃, —CCl₃. In certainembodiments, R⁴ is hydroxyalkyl, e.g., —CH₂OH, —CH₂CH₂OH, —CH₂OR^(f),—CH₂CH₂OR^(f). In certain embodiments, R⁴ is aminoalkyl, e.g., —CH₂NH₂,—CH₂CH₂NH₂, —CH₂NMe₂, —CH₂CH₂NMe₂, —CH₂N(R^(f))₂, —CH₂CH₂N(R^(f))₂.

In certain embodiments, R⁴ is optionally substituted acyl, e.g., —CHO,—CO₂H, or —C(═O)NH₂. In certain embodiments, R⁴ is —C(═O)R^(f),—C(═O)OR^(f), —C(═O)NH(R^(f)), or —C(═O)N(R^(f))₂. In certainembodiments, R⁴ is —C(═O)R^(f), and R^(f) is optionally substitutedalkyl, e.g., —C(═O)Me. In certain embodiments, R⁴ is —C(═O)R^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, R⁴ is—C(═O)R^(f), and R^(f) is optionally substituted carbocyclyl,heterocyclyl, aryl, or heteroaryl. In certain embodiments, R⁴ is—C(═O)OR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, R⁴ is —C(═O)OR^(f), and R^(f) is optionally substitutedalkenyl. In certain embodiments, R⁴ is —C(═O)OR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.In certain embodiments, R⁴ is —C(═O)N(R^(f))₂, and at least one R^(f) isoptionally substituted alkyl. In certain embodiments, R⁴ is—C(═O)NHR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, R⁴ is —C(═O)NHR^(f), and R^(f) is optionally substitutedalkenyl. In certain embodiments, R⁴ is —C(═O)NHR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.In certain embodiments, R⁴ is a nitrogen protecting group. In someembodiments, R⁴ is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl,acetyl, or Ts.

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

As generally defined herein, L⁴ is unsubstituted branched alkylene orsubstituted alkylene. In certain embodiments, L⁴ is unsubstitutedbranched alkylene. In some embodiments, L⁴ is unsubstituted branchedC₁₋₁₂ alkylene. In some embodiments, L⁴ is unsubstituted branched C₁₋₈alkylene. In some embodiments, L⁴ is unsubstituted branched C₁-6alkylene. In some embodiments, L⁴ is unsubstituted branched C₂₋₆alkylene. In some embodiments, L⁴ is unsubstituted branched C₃₋₆alkylene. In some embodiments, L⁴ is unsubstituted branched C₄₋₆ In someembodiments, L⁴ is unsubstituted branched C₅₋₆ alkylene. alkylene. Insome embodiments, L⁴ is unsubstituted branched C₁₋₅ alkylene. In someembodiments, L⁴ is unsubstituted branched C₂₋₅ alkylene. In someembodiments, L⁴ is unsubstituted branched C₃₋₅ alkylene. In someembodiments, L⁴ is unsubstituted branched C₄₋₅ alkylene. In someembodiments, L⁴ is unsubstituted branched C₁4 alkylene. In someembodiments, L⁴ is unsubstituted branched C₂₋₄ alkylene. In someembodiments, L⁴ is unsubstituted branched C₃₋₄ alkylene. In someembodiments, L⁴ is unsubstituted branched C₁₋₃ alkylene. In someembodiments, L⁴ is unsubstituted branched C₂₋₃ alkylene. In someembodiments, L⁴ is unsubstituted branched C₁₋₂ alkylene. In someembodiments, L⁴ is unsubstituted branched C₁ alkylene. In someembodiments, L⁴ is unsubstituted branched C₂ alkylene. In someembodiments, L⁴ is unsubstituted branched C₃ alkylene. In someembodiments, L⁴ is unsubstituted branched C₄ alkylene. In someembodiments, L⁴ is unsubstituted branched C₅ alkylene. In someembodiments, L⁴ is unsubstituted branched C₆ alkylene.

In certain embodiments, L⁴ is substituted alkylene. Substituted alkyleneincludes both branched and unbranched substituted alkylenes. In someembodiments, L⁴ is substituted C₁₋₁₂ alkylene. In some embodiments, L⁴is substituted C₁₋₈ alkylene. In some embodiments, L⁴ is substitutedC₁₋₆ alkylene. In some embodiments, L⁴ is substituted C₂₋₆ alkylene. Insome embodiments, L⁴ is substituted C₃₋₆ alkylene. In some embodiments,L⁴ is substituted alkylene, wherein the substituents are selected fromthe group consisting of alkyl, halogen, —OH, —OR^(f), —NH₂, —NHR^(f),and —N(R^(f))₂. In some embodiments, L⁴ is substituted alkylene, whereinthe substituents are selected from the group consisting of halogen, —OH,or —OR^(f). In some embodiments, L⁴ substituted alkylene, wherein thesubstituent or substituents are halogen (e.g., —F, —Cl, —Br).

As generally defined herein X⁴ is halogen, —OR^(f), —SR^(f), or—N(R^(f))₂. In certain embodiments, X⁴ is halogen or —OH. In someembodiments, X⁴ is —F or —OH. In certain embodiments, X⁴ is halogen. Insome embodiments, X⁴ is —F. In some embodiments, X⁴ is —Cl, —Br, or —I.

In certain embodiments, X⁴ is —OR^(f), e.g., —OH. In certainembodiments, X⁴ is —OR^(f), and R^(f) is optionally substituted alkyl.In certain embodiments, X⁴ is —OR^(f), and R^(f) is unsubstituted C₁₋₆alkyl. In certain embodiments, X⁴ is —OR^(f), and R^(f) is optionallysubstituted alkenyl. In certain embodiments, X⁴ is —OR^(f), and R^(f) isoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl optionally substituted heteroaryl. Incertain embodiments, X⁴ is —OR^(f), and R^(f) is unsubstitutedcarbocyclyl, unsubstituted heterocyclyl, unsubstituted arylunsubstituted heteroaryl. In certain embodiments, X⁴ is —OR^(f), andR^(f) is optionally substituted acyl, e.g., X⁴ is —OC(═O)R^(f),—OC(═O)OR^(f), or —OC(═O)N(R^(f))₂. In certain embodiments, X⁴ is—OR^(f), and R^(f) is an oxygen protecting group.

In certain embodiments, X⁴ is —SR^(f), e.g., —SH. In certainembodiments, X⁴ is —SR^(f), and R^(f) is optionally substituted alkyl.In certain embodiments, X⁴ is —SR^(f), and R^(f) is unsubstituted C₁₋₆alkyl. In certain embodiments, X⁴ is —SR^(f), and R^(f) is optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl optionally substituted heteroaryl. In certainembodiments, X⁴ is —SR^(f), and R^(f) is unsubstituted carbocyclyl,unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl.In certain embodiments, X⁴ is —SR^(f), and R^(f) is a sulfur protectinggroup.

In certain embodiments, X⁴ is —N(R^(f))₂, e.g., —NH₂, —NHR^(f). Incertain embodiments, X⁴ is —NH(R^(f)), and R^(f) is optionallysubstituted alkyl. In certain embodiments, X⁴ is —N(R^(f))₂, and atleast one R^(f) is optionally substituted alkyl. In certain embodiments,X⁴ is —NH(R^(f)), and R^(f) is unsubstituted alkyl. In certainembodiments, X⁴ is —N(R^(f))₂, and at least one R^(f) is unsubstitutedalkyl. In certain embodiments, X⁴ is —NHR^(f), and R^(f) is optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl. In certainembodiments, X⁴ is —NHR^(f), and R^(f) is unsubstituted carbocyclyl,unsubstituted heterocyclyl, unsubstituted aryl, or unsubstitutedheteroaryl. In certain embodiments, X⁴ is —NHR^(f), and R^(f) isoptionally substituted acyl, e.g., X⁴ is —NHC(═O)R^(f), —NHC(═O)OR^(f),or —NHC(═O)NHR^(f). In certain embodiments, X⁴ is —N(R^(f))₂, and atleast one R^(f) is a nitrogen protecting group. In certain embodiments,X⁴ is —N(R^(f))₂, and both R^(f) are joined to form an optionallysubstituted heterocyclic or optionally substituted heteroaryl ring. Incertain embodiments, X⁴ is —N(R^(f))₂, and both R^(f) are joined to forman unsubstituted heterocyclic or unsubstituted heteroaryl ring.

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Ring D is of formula:

In certain embodiments, Ring D is of formula:

In certain embodiments, Ring D is of formula:

In certain embodiments, Y is of formula:

As generally defined herein, L¹ is optionally substituted alkylene. Incertain embodiments, L is optionally substituted C₁₋₁₂ alkylene. In someembodiments, L is optionally substituted C₁₋₈ alkylene. In someembodiments, L¹ is optionally substituted C₁₋₆ alkylene. In someembodiments, L¹ is optionally substituted C₁₋₆ alkylene. In someembodiments, L¹ is optionally substituted C₂₋₆ alkylene. In someembodiments, L¹ is optionally substituted C₃₋₆ alkylene. In certainembodiments, L¹ is unsubstituted C₁₋₁₂ alkylene. In some embodiments, L¹is unsubstituted C₁₋₈ alkylene. In some embodiments, L¹ is unsubstitutedC₁₋₆ alkylene. In some embodiments, L¹ is unsubstituted C₂₋₆ alkylene.In some embodiments, L¹ is unsubstituted C₃₋₆ alkylene. In someembodiments, L¹ is unsubstituted C₁₋₆ alkylene. In some embodiments, L¹is unsubstituted C₂₋₆ alkylene. In some embodiments, L¹ is unsubstitutedC₃₋₆ alkylene. In some embodiments, L¹ is substituted alkylene, whereinthe substituents are selected from the group consisting of alkyl,halogen, —OH, —OR^(f), —NH₂, —NHR^(f), and —N(R^(f))₂. In certainembodiments, L¹ is —(CH₂)_(q)—, wherein q is 1, 2, 3, 4, 5, or 6.

As generally defined herein Ring D is carbocyclic or a heterocyclicring, wherein the heterocyclic ring contains one heteroatom, and theheteroatom is N. Ring D may be substituted with 0, 1, 2, 3, or 4 R^(D).In some embodiments, two R^(D) are attached geminally.

As generally defined herein, d is 0, 1, 2, 3, or 4. In certainembodiments, d is 0. In certain embodiments, d is 1. In certainembodiments, d is 2. In certain embodiments, d is 3. In certainembodiments, d is 4. In certain embodiments, d is 0, 1, 2, or 3. Incertain embodiments, d is 0, 1, or 2. In certain embodiments, d is 0or 1. In certain embodiments, d is 1, 2, 3, or 4. In certainembodiments, d is 2, 3, or 4. In certain embodiments, d is 3 or 4.

In certain embodiments, Ring D is carbocyclyl. e.g., optionallysubstituted C₃₋₆ carbocyclyl, optionally substituted C₃₋₄ carbocyclyl,optionally substituted C₄₋₅ carbocyclyl, or optionally substituted C₅₋₆carbocyclyl. In certain embodiments, Ring D is unsubstitutedcarbocyclyl, e.g., unsubstituted C₃₋₆ carbocyclyl. In some embodiments,Ring D is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In certain embodiments, Ring D is heterocyclyl with one heteroatom, andthe heteroatom is nitrogen. Ring D is optionally substitutedheterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl,optionally substituted 3-4 membered heterocyclyl, optionally substituted4-5 membered heterocyclyl, or optionally substituted 5-6 memberedheterocyclyl. In certain embodiments, Ring D is unsubstitutedheterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl,unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 memberedheterocyclyl, or unsubstituted 5-6 membered heterocyclyl. In someembodiments, Ring D is piperidinyl, dihydropyridinyl, pyrrolidinyl,azetidinyl, azepanyl, azocanyl, or aziridinyl. In some embodiments, RingD is piperidinyl or pyrrolidinyl.

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

or.

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

As generally defined herein, z is 0, 1, or 2. When z is 0, the ringcomprising E is a 5-membered ring. When z is 1, the ring comprising E isa 6-membered ring. When z is 2, the ring comprising z is a 7-memberedring. The ring comprising E may be substituted with 0, 1, 2, 3, or 4R^(D). In some embodiments, two R^(D) are attached geminally.

As generally defined herein, E is —O—, —S—, —N(R^(E))—, or —CH(R^(E))—.In certain embodiments, E is —N(R^(E))—, or —CH(R^(E))—. In someembodiments, E is —O—. In some embodiments, E is —S—. In someembodiments, E is —N(R^(E))—. In some embodiments, E is —CH(R^(E))—.

As generally defined herein, R^(E) is optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl, or optionally substituted heteroaryl.

In certain embodiments, R^(E) is optionally substituted carbocyclyl,e.g., optionally substituted C₃₋₆ carbocyclyl, optionally substitutedC₃₋₄ carbocyclyl, optionally substituted C₄₋₅ carbocyclyl, or optionallysubstituted C₅₋₆ carbocyclyl. In certain embodiments, R^(E) isunsubstituted carbocyclyl, e.g., unsubstituted C₃₋₆ carbocyclyl. In someembodiments, R^(E) is optionally substituted cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl. In certain embodiments, R^(E) is optionallysubstituted heterocyclyl, e.g., optionally substituted 3-6 memberedheterocyclyl, optionally substituted 3-4 membered heterocyclyl,optionally substituted 4-5 membered heterocyclyl, or optionallysubstituted 5-6 membered heterocyclyl. In certain embodiments, R^(E) isunsubstituted heterocyclyl, e.g., unsubstituted 3-6 memberedheterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl. Insome embodiments, R^(E) is optionally substituted piperidinyl,dihydropyridinyl, pyrrolidinyl, azetidinyl, azepanyl, azocanyl, oraziridinyl. In some embodiments, R^(E) is optionally substitutedpiperidinyl, pyrrolidinyl, or morpholinyl.

In certain embodiments, R^(E) is optionally substituted aryl, e.g.,optionally substituted phenyl. In certain embodiments, R^(E) isunsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments,R^(E) is optionally substituted heteroaryl, e.g., optionally substituted5-6 membered heteroaryl, or optionally substituted 9-10 memberedbicyclic heteroaryl. In certain embodiments, R^(E) is unsubstitutedheteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, orunsubstituted 9-10 membered bicyclic heteroaryl. In some embodiments,R^(E) is imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. In some embodiments, R^(E) is triazolyl, oxadiazolyl,thiadiazolyl, or tetrazolyl. In certain embodiments, R^(E) is 6-memberedheteroaryl. In some embodiments, R^(E) is pyridinyl. In someembodiments, R^(E) is pyridazinyl, pyrimidinyl, and pyrazinyl.

In certain embodiments, Y is of formula:

In certain embodiments, Y is of formula:

As generally defined Ring G is a bicyclic heterocyclic or bicyclicheteroaryl ring, wherein the rings share exactly two atoms. Ring G is afused bicyclic (e.g., quinoline, decahydroquinoline) sharing two atoms,as opposed to a bridged bicyclic (e.g., 7-azabicyclo[2.2.1]heptane)sharing more than 2 atoms, or spiro bicyclic (e.g.,3-azaspiro[5.5]undecane) sharing one atom.

In certain embodiments, Ring G is a bicyclic heterocyclic ring, whereinthe rings share exactly two atoms. In certain embodiments, Ring G is abicyclic heteroaryl ring, wherein the rings share exactly two atoms. Insome embodiments, Ring G is a 9-10 membered bicyclic heteroaryl. In someembodiments, Ring G comprises two fused 6-membered rings. In someembodiments, Ring G comprises two fused 5-membered rings. In someembodiments, Ring G comprises a 6-membered ring fused to a 5-memberedring. In some embodiments, Ring G is indolinyl, isoindolinyl,tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,decahydroquinolinyl, decahydroisoquinolinyl, decahydronaphthyridinyl,decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl,phthalimidyl, naphthalimidyl, 1H-benzo[e][1,4]diazepinyl,1,4,5,7-tetrahydro-pyrano[3,4-b]pyrrolyl,5,6-dihydro-4H-furo[3,2-b]pyrrolyl,2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl,4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, or1,2,3,4-tetrahydro-1,6-naphthyridinyl.

In certain embodiments, Ring G comprises Ring G¹ and Ring G², and Y isof formula:

wherein Ring G¹ monocyclic heterocyclyl or heteroaryl, Ring G² iscarbocyclyl, heterocyclyl aryl, or heteroaryl; and

is a single or double bond. In some embodiments,

is a single bond. In some embodiments,

is a double bond. Ring G¹ and Ring G² may together be substituted with0, 1, 2, 3, or 4 R^(D).

In certain embodiments, Ring G¹ is heterocyclyl, e.g., 3-6 memberedheterocyclyl, 3-4 membered heterocyclyl, 4-5 membered heterocyclyl, or5-6 membered heterocyclyl. In certain embodiments, Ring G¹ isunsubstituted heterocyclyl, e.g., unsubstituted 3-6 memberedheterocyclyl, unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5membered heterocyclyl, or unsubstituted 5-6 membered heterocyclyl. Insome embodiments, Ring G¹ is piperidinyl, dihydropyridinyl,pyrrolidinyl, azetidinyl, azepanyl, azocanyl, or aziridinyl. In someembodiments, Ring G¹ is piperidinyl or pyrrolidinyl. In someembodiments, Ring G¹ is piperazinyl, or morpholinyl.

In certain embodiments, Ring G¹ is heteroaryl. In certain embodiments,Ring G¹ is monocyclic heteroaryl. In certain embodiments, Ring G¹ is5-membered heteroaryl. In some embodiments, Ring G¹ is pyrrolyl,furanyl, or thiophenyl. In some embodiments, Ring G¹ is imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. In someembodiments, Ring G¹ is triazolyl, oxadiazolyl, thiadiazolyl, ortetrazolyl. In certain embodiments, Ring G¹ is 6-membered heteroaryl. Insome embodiments, Ring G¹ is pyridinyl. In some embodiments, Ring G¹ ispyridazinyl, pyrimidinyl, and pyrazinyl.

In certain embodiments, Ring G² is carbocyclyl, e.g., C₃₋₆ carbocyclyl,C₃₋₄ carbocyclyl, C₄₋₅ carbocyclyl, or C₅₋₆ carbocyclyl. In certainembodiments, Ring G² is unsubstituted carbocyclyl, e.g., unsubstitutedC₃₋₆ carbocyclyl. In some embodiments, Ring G² is cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, Ring G²is heterocyclyl, e.g., 3-6 membered heterocyclyl, 3-4 memberedheterocyclyl, 4-5 membered heterocyclyl, or 5-6 membered heterocyclyl.In certain embodiments, Ring G² is unsubstituted heterocyclyl, e.g.,unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 memberedheterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted5-6 membered heterocyclyl.

In certain embodiments, Ring G² is aryl, e.g., phenyl. In certainembodiments, Ring G² is unsubstituted aryl, e.g., unsubstituted phenyl.In certain embodiments, Ring G² is heteroaryl, e.g., 5-6 memberedheteroaryl. In certain embodiments, Ring G² is unsubstituted heteroaryl,e.g., unsubstituted 5-6 membered heteroaryl.

In certain embodiments Y is of formula:

In certain embodiments Y is of formula:

In certain embodiments Y is of formula:

In certain embodiments Y is of formula:

In certain embodiments Y is of formula:

R²

As generally defined herein, R² is hydrogen, halogen, or optionallysubstituted alkyl. In certain embodiments, the carbon to which R² isattached is in the (S)-configuration. In certain embodiments, the carbonto which R² is attached is in the (R)-configuration. In certainembodiments, R² is hydrogen, and the carbon to which R² is attached isin the (S)-configuration. In certain embodiments, R² is hydrogen, andthe carbon to which R² is attached is in the (R)-configuration. Incertain embodiments, R² is hydrogen. In certain embodiments, R² is anon-hydrogen group. In certain embodiments, R² is halogen. In certainembodiments, R² is —F. In certain embodiments, R² is —Cl, —Br, or —I.

In certain embodiments, R² is optionally substituted alkyl, e.g.,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₂ alkyl,optionally substituted C₂₋₃ alkyl, optionally substituted C₃₋₄ alkyl,optionally substituted C₄₋₅ alkyl, or optionally substituted C₅₋₆ alkyl.In certain embodiments, R² is unsubstituted alkyl, e.g., unsubstitutedC₁₋₆ alkyl, unsubstituted C₁₋₂ alkyl, unsubstituted C₂₋₃ alkyl,unsubstituted C₃₋₄ alkyl, unsubstituted C₄₋₅ alkyl, or unsubstitutedC₅₋₆ alkyl. In certain embodiments, R² is methyl. In certainembodiments, R² is ethyl, propyl, or butyl. In certain embodiments, R²is haloalkyl, e.g., —CHF₂, —CHC₂, —CH₂CHF₂, —CH₂CHCl₂. In certainembodiments, R² is perhaloalkyl, e.g., —CF₃, —CF₂CF₃, —CCl₃. In certainembodiments, R² is hydroxyalkyl, e.g., —CH₂OH, —CH₂CH₂OH, —CH₂OR^(f),—CH₂CH₂OR^(f). In certain embodiments, R² is aminoalkyl, e.g., —CH₂NH₂,—CH₂CH₂NH₂, —CH₂NMe₂, —CH₂CH₂NMe₂, —CH₂N(R^(f))₂, —CH₂CH₂N(R^(f))₂.

R^(A1) and R^(A2)

Compounds of Formula (I) comprise groups R^(A1) and R^(A2). As generallydefined herein, R^(A1) is hydrogen, halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, —OR^(f), —SR^(f), —N(R^(f))₂, —NO₂, or —CN.In certain embodiments, R^(A1) is —CH₂R^(M), wherein R^(M) is —CN,—N(R^(f))₂, or —CH₂N(R^(f))₂. In certain embodiments, R^(A2) is—CH₂R^(M), wherein R^(M) is —CN, —N(R^(f))₂, or —CH₂N(R^(f))₂.

In certain embodiments, R^(A1) is hydrogen. In certain embodiments,R^(A1) is a non-hydrogen group. In certain embodiments, R^(A1) ishalogen. In certain embodiments, R^(A1) is —F. In certain embodiments,R^(A) is —Cl, —Br, or —I. In certain embodiments, R^(A1) is —NO₂. Incertain embodiments, R^(A1) is —CN.

In certain embodiments, R^(A1) is optionally substituted alkyl, e.g.,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₂ alkyl,optionally substituted C₂₋₃ alkyl, optionally substituted C₃₋₄ alkyl,optionally substituted C₄₋₅ alkyl, or optionally substituted C₅₋₆ alkyl.In certain embodiments, R^(A1) is unsubstituted alkyl, e.g.,unsubstituted C₁₋₆ alkyl, unsubstituted C₁₋₂ alkyl, unsubstituted C₂₋₃alkyl, unsubstituted C₃₋₄ alkyl, unsubstituted C₄₋₅ alkyl, orunsubstituted C₅₋₆ alkyl. In certain embodiments, R^(A1) is methyl. Incertain embodiments, R^(A1) is ethyl, propyl, or butyl. In certainembodiments, R^(A1) is haloalkyl, e.g., —CHF₂, —CHCl₂, —CH₂CHF₂,—CH₂CHCl₂. In certain embodiments, R^(A1) is perhaloalkyl, e.g., —CF₃,—CF₂CF₃, —CCl₃. In certain embodiments, R^(A1) is hydroxyalkyl, e.g.,—CH₂OH, —CH₂CH₂OH, —CH₂OR^(f), —CH₂CH₂OR^(f). In certain embodiments,R^(A1) is aminoalkyl, e.g., —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NMe₂, —CH₂CH₂NMe₂,—CH₂N(R^(f))₂, —CH₂CH₂N(R^(f))₂.

In certain embodiments, R^(A1) is optionally substituted alkenyl, e.g.,optionally substituted C₂₋₆ alkenyl. In certain embodiments, R^(A1) isunsubstituted alkenyl, e.g., unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(A1) is vinyl, allyl, or prenyl. In certain embodiments,R^(A1) is optionally substituted alkynyl, e.g., optionally substitutedC₂₋₆ alkynyl. In certain embodiments, R^(A1) is unsubstituted alkynyl,e.g., unsubstituted C₂₋₆ alkynyl.

In certain embodiments, R^(A1) is optionally substituted carbocyclyl,e.g., optionally substituted C₃₋₆ carbocyclyl, optionally substitutedC₃₋₄ carbocyclyl, optionally substituted C₄₋₅ carbocyclyl, or optionallysubstituted C₅₋₆ carbocyclyl. In certain embodiments, R^(A1) isunsubstituted carbocyclyl, e.g., unsubstituted C₃₋₆ carbocyclyl. In someembodiments, R^(A1) is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In certain embodiments, R^(A1) is optionally substitutedheterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl,optionally substituted 3-4 membered heterocyclyl, optionally substituted4-5 membered heterocyclyl, or optionally substituted 5-6 memberedheterocyclyl. In certain embodiments, R^(A1) is unsubstitutedheterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl,unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 memberedheterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

In certain embodiments, R^(A1) is optionally substituted aryl, e.g.,optionally substituted phenyl. In certain embodiments, R^(A1) isunsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments,R^(A1) is optionally substituted heteroaryl, e.g., optionallysubstituted 5-6 membered heteroaryl, or optionally substituted 9-10membered bicyclic heteroaryl. In certain embodiments, R^(A1) isunsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl,or unsubstituted 9-10 membered bicyclic heteroaryl. In certainembodiments, R^(A1) is optionally substituted aralkyl, e.g., optionallysubstituted benzyl. In certain embodiments, R^(A1) is optionallysubstituted heteroaralkyl, e.g., methyl substituted with an optionallysubstituted 5-6 membered heteroaryl ring. In certain embodiments, R^(A1)is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certainembodiments, R^(A1) is unsubstituted heteroaralkyl, e.g., methylsubstituted with an unsubstituted 5-6 membered heteroaryl ring.

In certain embodiments, R^(A1) is optionally substituted acyl, e.g.,—CHO, —CO₂H, or —C(═O)NH₂. In certain embodiments, R^(A1) is—C(═O)R^(f), —C(═O)OR^(f), —C(═O)NH(R^(f)), or —C(═O)N(R^(f))₂. Incertain embodiments, R^(A1) is —C(═O)R^(f), and R^(f) is optionallysubstituted alkyl, e.g., —C(═O)Me. In certain embodiments, R^(A1) is—C(═O)R^(f), and R^(f) is optionally substituted alkenyl. In certainembodiments, R^(A1) is —C(═O)R^(f), and R^(f) is optionally substitutedcarbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments,R^(A1) is —C(═O)OR^(f), and R^(f) is optionally substituted alkyl. Incertain embodiments, R^(A1) is —C(═O)OR^(f), and R^(f) is optionallysubstituted alkenyl. In certain embodiments, R^(A1) is —C(═O)OR^(f), andR^(f) is optionally substituted carbocyclyl, heterocyclyl, aryl, orheteroaryl. In certain embodiments, R^(A1) is —C(═O)N(R^(f))₂, and atleast one R^(f) is optionally substituted alkyl. In certain embodiments,R^(A1) is —C(═O)NHR^(f), and R^(f) is optionally substituted alkyl. Incertain embodiments, R^(A1) is —C(═O)NHR^(f), and R^(f) is optionallysubstituted alkenyl. In certain embodiments, R^(A1) is —C(═O)NHR^(f),and R^(f) is optionally substituted carbocyclyl, heterocyclyl, aryl, orheteroaryl.

In certain embodiments, R^(A1) is —OR^(f), e.g., —OH. In certainembodiments, R^(A1) is —OR^(f), and R^(f) is optionally substitutedalkyl. In certain embodiments, R^(A1) is —OR^(f), and R^(f) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A1) is —OR^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, R^(A1)is —OR^(f), and R^(f) is optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl optionallysubstituted heteroaryl. In certain embodiments, R^(A1) is —OR^(f), andR^(f) is unsubstituted carbocyclyl, unsubstituted heterocyclyl,unsubstituted aryl unsubstituted heteroaryl. In certain embodiments,R^(A1) is —OR^(f), and R^(f) is optionally substituted acyl, e.g.,R^(A1) is —OC(═O)R^(f), —OC(═O)OR^(f), or —OC(═O)N(R^(f))₂. In certainembodiments, R^(A1) is —OR^(f), and R^(f) is an oxygen protecting group.

In certain embodiments, R^(A1) is —SR^(f), e.g., —SH. In certainembodiments, R^(A1) is —SR^(f), and R^(f) is optionally substitutedalkyl. In certain embodiments, R^(A1) is —SR^(f), and R^(f) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A1) is —SR^(f), andR^(f) is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl optionally substitutedheteroaryl. In certain embodiments, R^(A1) is —SR^(f), and R^(f) isunsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstitutedaryl unsubstituted heteroaryl. In certain embodiments, R^(A) is —SR^(f),and R^(f) is a sulfur protecting group.

In certain embodiments, R^(A1) is —N(R^(f))₂, e.g., —NH₂, —NHR^(f). Incertain embodiments, R^(A1) is —NH(R^(f)), and R^(f) is optionallysubstituted alkyl. In certain embodiments, R^(A1) is —N(R^(f))₂, and atleast one R^(f) is optionally substituted alkyl. In certain embodiments,R^(A1) is —NH(R^(f)), and R^(f) is unsubstituted alkyl. In certainembodiments, R^(A1) is —N(R^(f))₂, and at least one R^(f) isunsubstituted alkyl. In certain embodiments, R^(A1) is —NHR^(f), andR^(f) is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl. In certain embodiments, R^(A1) is —NHR^(f), and R^(f) isunsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstitutedaryl, or unsubstituted heteroaryl. In certain embodiments, R^(A1) is—NHR^(f), and R^(f) is optionally substituted acyl, e.g., R^(A1) is—NHC(═O)R^(f), —NHC(═O)OR^(f), or —NHC(═O)NHR^(f). In certainembodiments, R^(A1) is —N(R^(f))₂, and at least one R^(f) is a nitrogenprotecting group. In certain embodiments, R^(A1) is —N(R^(f))₂, and bothR^(f) are joined to form an optionally substituted heterocyclic oroptionally substituted heteroaryl ring. In certain embodiments, R^(A1)is —N(R^(f))₂, and both R^(f) are joined to form an unsubstitutedheterocyclic or unsubstituted heteroaryl ring.

As generally defined herein, R^(A2) is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, —OR^(f), —SR^(f),—N(R^(f))₂, —NO₂, or —CN.

In certain embodiments, R^(A2) is hydrogen. In certain embodiments,R^(A2) is a non-hydrogen group. In certain embodiments, R^(A2) ishalogen. In certain embodiments, R^(A2) is —F. In certain embodiments,R^(A2) is —Cl, —Br, or —I. In certain embodiments, R^(A2) is —NO₂. Incertain embodiments, R^(A2) is —CN.

In certain embodiments, R^(A2) is optionally substituted alkyl, e.g.,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₂ alkyl,optionally substituted C₂₋₃ alkyl, optionally substituted C₃₋₄ alkyl,optionally substituted C₄₋₅ alkyl, or optionally substituted C₅₋₆ alkyl.In certain embodiments, R^(A2) is unsubstituted alkyl, e.g.,unsubstituted C₁₋₆ alkyl, unsubstituted C₁₋₂ alkyl, unsubstituted C₂₋₃alkyl, unsubstituted C₃₋₄ alkyl, unsubstituted C₄₋₅ alkyl, orunsubstituted C₅₋₆ alkyl. In certain embodiments, R^(A2) is methyl. Incertain embodiments, R^(A2) is ethyl, propyl, or butyl. In certainembodiments, R^(A2) is haloalkyl, e.g., —CHF₂, —CHCl₂, —CH₂CHF₂,—CH₂CHCl₂. In certain embodiments, R^(A2) is perhaloalkyl, e.g., —CF₃,—CF₂CF₃, —CCl₃. In certain embodiments, R^(A2) is hydroxyalkyl, e.g.,—CH₂OH, —CH₂CH₂OH, —CH₂OR^(f), —CH₂CH₂OR^(f). In certain embodiments,R^(A2) is aminoalkyl, e.g., —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NMe₂, —CH₂CH₂NMe₂,—CH₂N(R^(f))₂, —CH₂CH₂N(R^(f))₂.

In certain embodiments, R^(A2) is optionally substituted alkenyl, e.g.,optionally substituted C₂₋₆ alkenyl. In certain embodiments, R^(A2) isunsubstituted alkenyl, e.g., unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(A2) is vinyl, allyl, or prenyl. In certain embodiments,R^(A2) is optionally substituted alkynyl, e.g., optionally substitutedC₂₋₆ alkynyl. In certain embodiments, R^(A2) is unsubstituted alkynyl,e.g., unsubstituted C₂₋₆ alkynyl.

In certain embodiments, R^(A2) is optionally substituted carbocyclyl,e.g., optionally substituted C₃₋₆ carbocyclyl, optionally substitutedC₃₋₄ carbocyclyl, optionally substituted C₄₋₅ carbocyclyl, or optionallysubstituted C₅₋₆ carbocyclyl. In certain embodiments, R^(A2) isunsubstituted carbocyclyl, e.g., unsubstituted C₃₋₆ carbocyclyl. In someembodiments, R^(A2) is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In certain embodiments, R^(A2) is optionally substitutedheterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl,optionally substituted 3-4 membered heterocyclyl, optionally substituted4-5 membered heterocyclyl, or optionally substituted 5-6 memberedheterocyclyl. In certain embodiments, R^(A2) is unsubstitutedheterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl,unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 memberedheterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

In certain embodiments, R^(A2) is optionally substituted aryl, e.g.,optionally substituted phenyl. In certain embodiments, R^(A2) isunsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments,R^(A2) is optionally substituted heteroaryl, e.g., optionallysubstituted 5-6 membered heteroaryl, or optionally substituted 9-10membered bicyclic heteroaryl. In certain embodiments, R^(A2) isunsubstituted heteroaryl, e.g., unsubstituted 5-6 membered heteroaryl,or unsubstituted 9-10 membered bicyclic heteroaryl. In certainembodiments, R^(A2) is optionally substituted aralkyl, e.g., optionallysubstituted benzyl. In certain embodiments, R^(A2) is optionallysubstituted heteroaralkyl, e.g., methyl substituted with an optionallysubstituted 5-6 membered heteroaryl ring. In certain embodiments, R^(A2)is unsubstituted aralkyl, e.g., unsubstituted benzyl. In certainembodiments, R^(A2) is unsubstituted heteroaralkyl, e.g., methylsubstituted with an unsubstituted 5-6 membered heteroaryl ring.

In certain embodiments, R^(A2) is optionally substituted acyl, e.g.,—CHO, —CO₂H, or —C(═O)NH₂. In certain embodiments, R^(A2) is—C(═O)R^(f), —C(═O)OR^(f), —C(═O)NH(R^(f)), or —C(═O)N(R^(f))₂. Incertain embodiments, R^(A2) is —C(═O)R^(f), and R^(f) is optionallysubstituted alkyl, e.g., —C(═O)Me. In certain embodiments, R^(A2) is—C(═O)R^(f), and R^(f) is optionally substituted alkenyl. In certainembodiments, R^(A2) is —C(═O)R^(f), and R^(f) is optionally substitutedcarbocyclyl, heterocyclyl, aryl, or heteroaryl. In certain embodiments,R^(A2) is —C(═O)OR^(f), and R^(f) is optionally substituted alkyl. Incertain embodiments, R^(A2) is —C(═O)OR^(f), and R^(f) is optionallysubstituted alkenyl. In certain embodiments, R^(A2) is —C(═O)OR^(f), andR^(f) is optionally substituted carbocyclyl, heterocyclyl, aryl, orheteroaryl. In certain embodiments, R^(A2) is —C(═O)N(R^(f))₂, and atleast one R^(f) is optionally substituted alkyl. In certain embodiments,R^(A2) is —C(═O)NHR^(f), and R^(f) is optionally substituted alkyl. Incertain embodiments, R^(A2) is —C(═O)NHR^(f), and R^(f) is optionallysubstituted alkenyl. In certain embodiments, R^(A2) is —C(═O)NHR^(f),and R^(f) is optionally substituted carbocyclyl, heterocyclyl, aryl, orheteroaryl.

In certain embodiments, R^(A2) is —OR^(f), e.g., —OH. In certainembodiments, R^(A2) is —OR^(f), and R^(f) is optionally substitutedalkyl. In certain embodiments, R^(A2) is —OR^(f), and R^(f) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A2) is —OR^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, R^(A2)is —OR^(f), and R^(f) is optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl optionallysubstituted heteroaryl. In certain embodiments, R^(A2) is —OR^(f), andR^(f) is unsubstituted carbocyclyl, unsubstituted heterocyclyl,unsubstituted aryl unsubstituted heteroaryl. In certain embodiments,R^(A2) is —OR^(f), and R^(f) is optionally substituted acyl, e.g.,R^(A2) is —OC(═O)R^(f), —OC(═O)OR^(f), or —OC(═O)N(R^(f))₂. In certainembodiments, R^(A2) is —OR^(f), and R^(f) is a sulfur protecting group.

In certain embodiments, R^(A2) is —SR^(f), e.g., —SH. In certainembodiments, R^(A2) is —SR^(f), and R^(f) is optionally substitutedalkyl. In certain embodiments, R^(A2) is —SR^(f), and R^(f) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(A2) is —SR^(f), andR^(f) is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl optionally substitutedheteroaryl. In certain embodiments, R^(A2) is —SR^(f), and R^(f) isunsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstitutedaryl unsubstituted heteroaryl. In certain embodiments, R^(A2) is—SR^(f), and R^(f) is an oxygen protecting group.

In certain embodiments, R^(A2) is —N(R^(f))₂, e.g., —NH₂, —NHR^(f). Incertain embodiments, R^(A2) is —NH(R^(f)), and R^(f) is optionallysubstituted alkyl. In certain embodiments, R^(A2) is —N(R^(f))₂, and atleast one R^(f) is optionally substituted alkyl. In certain embodiments,R^(A2) is —NH(R^(f)), and R^(f) is unsubstituted alkyl. In certainembodiments, R^(A2) is —N(R^(f))₂, and at least one R^(f) isunsubstituted alkyl. In certain embodiments, R^(A2) is —NHR^(f), andR^(f) is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl. In certain embodiments, R^(A2) is —NHR^(f), and R^(f) isunsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstitutedaryl, or unsubstituted heteroaryl. In certain embodiments, R^(A2) is—NHR^(f), and R^(f) is optionally substituted acyl, e.g., R^(A2) is—NHC(═O)R^(f), —NHC(═O)OR^(f), or —NHC(═O)NHR^(f). In certainembodiments, R^(A2) is —N(R^(f))₂, and at least one R^(f) is a nitrogenprotecting group. In certain embodiments, R^(A2) is —N(R^(f))₂, and bothR^(f) are joined to form an optionally substituted heterocyclic oroptionally substituted heteroaryl ring. In certain embodiments, R^(A2)is —N(R^(f))₂, and both R^(f) are joined to form an unsubstitutedheterocyclic or unsubstituted heteroaryl ring.

In some embodiments, R^(A1) and R^(A2) are the same. In someembodiments, R^(A1) and R^(A2) are different. In certain embodiments,both R^(A1) and R^(A2) are hydrogen. In certain embodiments, both R^(A1)and R^(A2) are optionally substituted halogen. In certain embodiments,both R^(A1) and R^(A2) are optionally substituted alkyl. In certainembodiments, both R^(A1) and R^(A2) are optionally substituted C₁₋₆alkyl. In certain embodiments, both R^(A1) and R^(A2) are unsubstitutedC₁₋₆ alkyl. In certain embodiments, both R^(A1) and R^(A2) are methyl.

R^(B) and X¹

As generally defined herein, R^(B) is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, —OR^(f), —SR^(f),—N(R^(f))₂, —NO₂, or —CN. In certain embodiments, R^(B) is —CH₂R^(M),wherein R^(M) is —CN, —N(R^(f))₂, or —CH₂N(R^(f))₂.

In certain embodiments, R^(B) is hydrogen. In certain embodiments, R^(B)is a non-hydrogen group. In certain embodiments, R^(B) is halogen. Incertain embodiments, R^(B) is —F. In certain embodiments, R^(B) is —Cl,—Br, or —I. In certain embodiments, R^(B) is —NO₂. In certainembodiments, R^(B) is —CN.

In certain embodiments, R^(B) is optionally substituted alkyl, e.g.,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₂ alkyl,optionally substituted C₂₋₃ alkyl, optionally substituted C₃₋₄ alkyl,optionally substituted C₄₋₅ alkyl, or optionally substituted C₅₋₆ alkyl.In certain embodiments, R^(B) is unsubstituted alkyl, e.g.,unsubstituted C₁₋₆ alkyl, unsubstituted C₁₋₂ alkyl, unsubstituted C₂₋₃alkyl, unsubstituted C₃₋₄ alkyl, unsubstituted C₄₋₅ alkyl, orunsubstituted C₅₋₆ alkyl. In certain embodiments, R^(B) is methyl. Incertain embodiments, R^(B) is ethyl, propyl, or butyl. In certainembodiments, R^(B) is haloalkyl, e.g., —CHF₂, —CHCl₂, —CH₂CHF₂,—CH₂CHCl₂. In certain embodiments, R^(B) is perhaloalkyl, e.g., —CF₃,—CF₂CF₃, —CCl₃. In certain embodiments, R^(B) is hydroxyalkyl, e.g.,—CH₂OH, —CH₂CH₂OH, —CH₂OR^(f), —CH₂CH₂OR^(f). In certain embodiments,R^(B) is aminoalkyl, e.g., —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NMe₂, —CH₂CH₂NMe₂,—CH₂N(R^(f))₂, —CH₂CH₂N(R^(f))₂.

In certain embodiments, R^(B) is optionally substituted alkenyl, e.g.,optionally substituted C₂₋₆ alkenyl. In certain embodiments, R^(B) isunsubstituted alkenyl, e.g., unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(B) is vinyl, allyl, or prenyl. In certain embodiments,R^(B) is optionally substituted alkynyl, e.g., optionally substitutedC₂₋₆ alkynyl. In certain embodiments, R^(B) is unsubstituted alkynyl,e.g., unsubstituted C₂₋₆ alkynyl.

In certain embodiments, R^(B) is optionally substituted carbocyclyl,e.g., optionally substituted C₃₋₆ carbocyclyl, optionally substitutedC₃₋₄ carbocyclyl, optionally substituted C₄₋₅ carbocyclyl, or optionallysubstituted C₅₋₆ carbocyclyl. In certain embodiments, R^(B) isunsubstituted carbocyclyl, e.g., unsubstituted C₃₋₆ carbocyclyl. In someembodiments, R^(B) is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In certain embodiments, R^(B) is optionally substitutedheterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl,optionally substituted 3-4 membered heterocyclyl, optionally substituted4-5 membered heterocyclyl, or optionally substituted 5-6 memberedheterocyclyl. In certain embodiments, R^(B) is unsubstitutedheterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl,unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 memberedheterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

In certain embodiments, R^(B) is optionally substituted aryl, e.g.,optionally substituted phenyl. In certain embodiments, R^(B) isunsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments,R^(B) is optionally substituted heteroaryl, e.g., optionally substituted5-6 membered heteroaryl, or optionally substituted 9-10 memberedbicyclic heteroaryl. In certain embodiments, R^(B) is unsubstitutedheteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, orunsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments,R^(B) is optionally substituted aralkyl, e.g., optionally substitutedbenzyl. In certain embodiments, R^(B) is optionally substitutedheteroaralkyl, e.g., methyl substituted with an optionally substituted5-6 membered heteroaryl ring. In certain embodiments, R^(B) isunsubstituted aralkyl, e.g., unsubstituted benzyl. In certainembodiments, R^(B) is unsubstituted heteroaralkyl, e.g., methylsubstituted with an unsubstituted 5-6 membered heteroaryl ring.

In certain embodiments, R^(B) is optionally substituted acyl, e.g.,—CHO, —CO₂H, or —C(═O)NH₂. In certain embodiments, R^(B) is —C(═O)R^(f),—C(═O)OR^(f), —C(═O)NH(R^(f)), or —C(═O)N(R^(f))₂. In certainembodiments, R^(B) is —C(═O)R^(f), and R^(f) is optionally substitutedalkyl, e.g., —C(═O)Me. In certain embodiments, R^(B) is —C(═O)R^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, R^(B)is —C(═O)R^(f), and R^(f) is optionally substituted carbocyclyl,heterocyclyl, aryl, or heteroaryl. In certain embodiments, R^(B) is—C(═O)OR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, R^(B) is —C(═O)OR^(f), and R^(f) is optionally substitutedalkenyl. In certain embodiments, R^(B) is —C(═O)OR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.In certain embodiments, R^(B) is —C(═O)N(R^(f))₂, and at least one R^(f)is optionally substituted alkyl. In certain embodiments, R^(B) is—C(═O)NHR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, R^(B) is —C(═O)NHR^(f), and R^(f) is optionally substitutedalkenyl. In certain embodiments, R^(B) is —C(═O)NHR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

In certain embodiments, R^(B) is —OR^(f), e.g., —OH. In certainembodiments, R^(B) is —OR^(f), and R^(f) is optionally substitutedalkyl. In certain embodiments, R^(B) is —OR^(f), and R^(f) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(B) is —OR^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, R^(B)is —OR^(f), and R^(f) is optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl optionallysubstituted heteroaryl. In certain embodiments, R^(B) is —OR^(f), andR^(f) is unsubstituted carbocyclyl, unsubstituted heterocyclyl,unsubstituted aryl unsubstituted heteroaryl. In certain embodiments,R^(B) is —OR^(f), and R^(f) is optionally substituted acyl, e.g., R^(B)is —OC(═O)R^(f), —OC(═O)OR^(f), or —OC(═O)N(R^(f))₂. In certainembodiments, R^(B) is —OR^(f), and R^(f) is an oxygen protecting group.

In certain embodiments, R^(B) is —SR^(f), e.g., —SH. In certainembodiments, R^(B) is —SR^(f), and R^(f) is optionally substitutedalkyl. In certain embodiments, R^(B) is —SR^(f), and R^(f) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(B) is —SR^(f), andR^(f) is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl optionally substitutedheteroaryl. In certain embodiments, R^(B) is —SR^(f), and R^(f) isunsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstitutedaryl unsubstituted heteroaryl. In certain embodiments, R^(B) is —SR^(f),and R^(f) is a sulfur protecting group.

In certain embodiments, R^(B) is —N(R^(f))₂, e.g., —NH₂, —NHR^(f). Incertain embodiments, R^(B) is —NH(R^(f)), and R^(f) is optionallysubstituted alkyl. In certain embodiments, R^(B) is —N(R^(f))₂, and atleast one R^(f) is optionally substituted alkyl. In certain embodiments,R^(B) is —NH(R^(f)), and R^(f) is unsubstituted alkyl. In certainembodiments, R^(B) is —N(R^(f))₂, and at least one R^(f) isunsubstituted alkyl. In certain embodiments, R^(B) is —NHR^(f), andR^(f) is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl. In certain embodiments, R^(B) is —NHR^(f), and R^(f) isunsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstitutedaryl, or unsubstituted heteroaryl. In certain embodiments, R^(B) is—NHR^(f), and R^(f) is optionally substituted acyl, e.g., R^(B) is—NHC(═O)R^(f), —NHC(═O)OR^(f), or —NHC(═O)NHR^(f). In certainembodiments, R^(B) is —N(R^(f))₂, and at least one R^(f) is a nitrogenprotecting group. In certain embodiments, R^(B) is —N(R^(f))₂, and bothR^(f) are joined to form an optionally substituted heterocyclic oroptionally substituted heteroaryl ring. In certain embodiments, R^(B) is—N(R^(f))₂, and both R^(f) are joined to form an unsubstitutedheterocyclic or unsubstituted heteroaryl ring.

As generally defined herein, X¹ is N or CR⁵, wherein R⁵ is hydrogen,halogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted acyl, —OR^(f),—SR^(f), —N(R^(f))₂, —NO₂, or —CN.

In certain embodiments, X¹ is N. In certain embodiments, X¹ is CR⁵. Insome embodiments, X¹ is CMe.

As generally defined herein, R⁵ is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, —OR^(f), —SR^(f),—N(R^(f))₂, —NO₂, or —CN. In certain embodiments, R⁵ is —CH₂R^(M),wherein R^(M) is —CN, —N(R^(f))₂, or —CH₂N(R^(f))₂.

In certain embodiments, R⁵ is hydrogen. In certain embodiments, R⁵ is anon-hydrogen group. In certain embodiments, R⁵ is halogen. In certainembodiments, R⁵ is —F. In certain embodiments, R⁵ is —Cl, -⁵r, or —I. Incertain embodiments, R⁵ is —NO₂. In certain embodiments, R⁵ is —CN.

In certain embodiments, R⁵ is optionally substituted alkyl, e.g.,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₂ alkyl,optionally substituted C₂₋₃ alkyl, optionally substituted C₃₋₄ alkyl,optionally substituted C₄₋₅ alkyl, or optionally substituted C₅₋₆ alkyl.In certain embodiments, R⁵ is unsubstituted alkyl, e.g., unsubstitutedC₁₋₆ alkyl, unsubstituted C₁₋₂ alkyl, unsubstituted C₂₋₃ alkyl,unsubstituted C₃₋₄ alkyl, unsubstituted C₄₋₅ alkyl, or unsubstitutedC₅₋₆ alkyl. In certain embodiments, R⁵ is methyl. In certainembodiments, R⁵ is ethyl, propyl, or butyl. In certain embodiments, R⁵is haloalkyl, e.g., —CHF₂, —CHC₂, —CH₂CHF₂, —CH₂CHCl₂. In certainembodiments, R⁵ is perhaloalkyl, e.g., —CF₃, —CF₂CF₃, —CCl₃. In certainembodiments, R⁵ is hydroxyalkyl, e.g., —CH₂OH, —CH₂CH₂OH, —CH₂OR^(f),—CH₂CH₂OR^(f). In certain embodiments, R⁵ is aminoalkyl, e.g., —CH₂NH₂,—CH₂CH₂NH₂, —CH₂NMe₂, —CH₂CH₂NMe₂, —CH₂N(R^(f))₂, —CH₂CH₂N(R^(f))₂.

In certain embodiments, R⁵ is optionally substituted alkenyl, e.g.,optionally substituted C₂₋₆ alkenyl. In certain embodiments, R⁵ isunsubstituted alkenyl, e.g., unsubstituted C₂₋₆ alkenyl. In certainembodiments, R⁵ is vinyl, allyl, or prenyl. In certain embodiments, R⁵is optionally substituted alkynyl, e.g., optionally substituted C₂₋₆alkynyl. In certain embodiments, R⁵ is unsubstituted alkynyl, e.g.,unsubstituted C₂₋₆ alkynyl.

In certain embodiments, R⁵ is optionally substituted carbocyclyl, e.g.,optionally substituted C₃₋₆ carbocyclyl, optionally substituted C₃₋₄carbocyclyl, optionally substituted C₄₋₅ carbocyclyl, or optionallysubstituted C₅₋₆ carbocyclyl. In certain embodiments, R⁵ isunsubstituted carbocyclyl, e.g., unsubstituted C₃₋₆ carbocyclyl. In someembodiments, R⁵ is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.In certain embodiments, R⁵ is optionally substituted heterocyclyl, e.g.,optionally substituted 3-6 membered heterocyclyl, optionally substituted3-4 membered heterocyclyl, optionally substituted 4-5 memberedheterocyclyl, or optionally substituted 5-6 membered heterocyclyl. Incertain embodiments, R⁵ is unsubstituted heterocyclyl, e.g.,unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 memberedheterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted5-6 membered heterocyclyl.

In certain embodiments, R⁵ is optionally substituted aryl, e.g.,optionally substituted phenyl. In certain embodiments, R⁵ isunsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments,R⁵ is optionally substituted heteroaryl, e.g., optionally substituted5-6 membered heteroaryl, or optionally substituted 9-10 memberedbicyclic heteroaryl. In certain embodiments, R⁵ is unsubstitutedheteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, orunsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments,R⁵ is optionally substituted aralkyl, e.g., optionally substitutedbenzyl. In certain embodiments, R⁵ is optionally substitutedheteroaralkyl, e.g., methyl substituted with an optionally substituted5-6 membered heteroaryl ring. In certain embodiments, R⁵ isunsubstituted aralkyl, e.g., unsubstituted benzyl. In certainembodiments, R⁵ is unsubstituted heteroaralkyl, e.g., methyl substitutedwith an unsubstituted 5-6 membered heteroaryl ring.

In certain embodiments, R⁵ is optionally substituted acyl, e.g., —CHO,—CO₂H, or —C(═O)NH₂. In certain embodiments, R⁵ is —C(═O)R^(f),—C(═O)OR^(f), —C(═O)NH(R^(f)), or —C(═O)N(R^(f))₂. In certainembodiments, R⁵ is —C(═O)R^(f), and R^(f) is optionally substitutedalkyl, e.g., —C(═O)Me. In certain embodiments, R⁵ is —C(═O)R^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, R⁵ is—C(═O)R^(f), and R^(f) is optionally substituted carbocyclyl,heterocyclyl, aryl, or heteroaryl. In certain embodiments, R⁵ is—C(═O)OR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, R⁵ is —C(═O)OR^(f), and R^(f) is optionally substitutedalkenyl. In certain embodiments, R⁵ is —C(═O)OR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.In certain embodiments, R⁵ is —C(═O)N(R^(f))₂, and at least one R^(f) isoptionally substituted alkyl. In certain embodiments, R⁵ is—C(═O)NHR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, R⁵ is —C(═O)NHR^(f), and R^(f) is optionally substitutedalkenyl. In certain embodiments, R⁵ is —C(═O)NHR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

In certain embodiments, R⁵ is —OR^(f), e.g., —OH. In certainembodiments, R⁵ is —OR^(f), and R^(f) is optionally substituted alkyl.In certain embodiments, R⁵ is —OR^(f), and R^(f) is unsubstituted C₁₋₆alkyl. In certain embodiments, R⁵ is —OR^(f), and R^(f) is optionallysubstituted alkenyl. In certain embodiments, R⁵ is —OR^(f), and R^(f) isoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl optionally substituted heteroaryl. Incertain embodiments, R⁵ is —OR^(f), and R^(f) is unsubstitutedcarbocyclyl, unsubstituted heterocyclyl, unsubstituted arylunsubstituted heteroaryl. In certain embodiments, R⁵ is —OR^(f), andR^(f) is optionally substituted acyl, e.g., R⁵ is —OC(═O)R^(f),—OC(═O)OR^(f), or —OC(═O)N(R^(f))₂. In certain embodiments, R⁵ is—OR^(f), and R^(f) is an oxygen protecting group.

In certain embodiments, R⁵ is —SR^(f), e.g., —SH. In certainembodiments, R⁵ is —SR, and R^(f) is optionally substituted alkyl. Incertain embodiments, R⁵ is —SR^(f), and R^(f) is unsubstituted C₁₋₆alkyl. In certain embodiments, R⁵ is —SR^(f), and R^(f) is optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl optionally substituted heteroaryl. In certainembodiments, R⁵ is —SR^(f), and R^(f) is unsubstituted carbocyclyl,unsubstituted heterocyclyl, unsubstituted aryl unsubstituted heteroaryl.In certain embodiments, R⁵ is —SR^(f), and R^(f) is a sulfur protectinggroup.

In certain embodiments, R⁵ is —N(R^(f))₂, e.g., —NH₂, —NHR^(f). Incertain embodiments, R⁵ is —NH(R^(f)), and R^(f) is optionallysubstituted alkyl. In certain embodiments, R⁵ is —N(R^(f))₂, and atleast one R^(f) is optionally substituted alkyl. In certain embodiments,R⁵ is —NH(R^(f)), and R^(f) is unsubstituted alkyl. In certainembodiments, R⁵ is —N(R^(f))₂, and at least one R^(f) is unsubstitutedalkyl. In certain embodiments, R⁵ is —NHR^(f), and R^(f) is optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, or optionally substituted heteroaryl. In certainembodiments, R⁵ is —NHR^(f), and R^(f) is unsubstituted carbocyclyl,unsubstituted heterocyclyl, unsubstituted aryl, or unsubstitutedheteroaryl. In certain embodiments, R⁵ is —NHR^(f), and R^(f) isoptionally substituted acyl, e.g., R⁵ is —NHC(═O)R^(f), —NHC(═O)OR^(f),or —NHC(═O)NHR^(f). In certain embodiments, R⁵ is —N(R^(f))₂, and atleast one R^(f) is a nitrogen protecting group. In certain embodiments,R⁵ is —N(R^(f))₂, and both R^(f) are joined to form an optionallysubstituted heterocyclic or optionally substituted heteroaryl ring. Incertain embodiments, R⁵ is —N(R^(f))₂, and both R^(f) are joined to forman unsubstituted heterocyclic or unsubstituted heteroaryl ring.

In some embodiments, X¹ is CR⁵, and R^(B) and R⁵ are the same. In someembodiments, X¹ is CR⁵, and R^(B) and R⁵ are different. In certainembodiments, X¹ is CR⁵, and both R^(B) and R⁵ are hydrogen. In certainembodiments, X¹ is CR⁵, and both R^(B) and R⁵ are optionally substitutedhalogen. In certain embodiments, X¹ is CR⁵, and both R^(B) and R⁵ areoptionally substituted alkyl. In certain embodiments, X¹ is CR⁵, andboth R^(B) and R⁵ are optionally substituted C₁₋₆ alkyl. In certainembodiments, X¹ is CR⁵, and both R^(B) and R⁵ are unsubstituted C₁₋₆alkyl. In certain embodiments, X¹ is CR⁵, and both R^(B) and R⁵ aremethyl.

Ring C and R^(C)

As generally defined herein, Ring C is aryl or heteroaryl. Ring C may besubstituted by 1, 2, 3, or 4 Rc. As generally defined herein, c is 0, 1,2, 3, or 4. In certain embodiments, c is 0. In certain embodiments, cis 1. In certain embodiments, c is 2. In certain embodiments, c is 3. Incertain embodiments, c is 4. In certain embodiments, c is 0, 1, 2, or 3.In certain embodiments, c is 0, 1, or 2. In certain embodiments, c is 0or 1. In certain embodiments, c is 1, 2, 3, or 4. In certainembodiments, c is 2, 3, or 4. In certain embodiments, c is 3 or 4.

In certain embodiments, Ring C is aryl. In certain embodiments, Ring Cis monocyclic aryl. In certain embodiments, Ring C is phenyl. In certainembodiments, Ring C is bicyclic aryl. In certain embodiments, Ring C isnaphthyl.

In certain embodiments, Ring C is heteroaryl. In certain embodiments,Ring C is monocyclic heteroaryl. In certain embodiments, Ring C is5-membered heteroaryl. In some embodiments, Ring C is pyrrolyl, furanyl,or thiophenyl. In some embodiments, Ring C is imidazolyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. In some embodiments,Ring C is triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. Incertain embodiments, Ring C is 6-membered heteroaryl. In someembodiments, Ring C is pyridinyl. In some embodiments, Ring C ispyridazinyl, pyrimidinyl, and pyrazinyl. In certain embodiments, Ring Cis bicyclic heteroaryl. In certain embodiments, Ring C is 9- to10-membered bicyclic heteroaryl. In some embodiments, Ring C is indolyl,isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl,isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl,benzisothiazolyl, benzthiadiazolyl, indolizinyl, or purinyl. In someembodiments, Ring C is naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, or quinazolinyl.

In certain embodiments, Ring C is of formula:

In certain embodiments, Ring C is of formula:

In certain embodiments, Ring C is of formula:

In certain embodiments, Ring C is of formula:

In certain embodiments, Ring C is of formula:

In certain embodiments, Ring C is of formula:

In certain embodiments, Ring C is of formula:

In certain embodiments, Ring C is of formula:

In certain embodiments, Ring C is of formula:

In certain embodiments, Ring C is of formula:

As generally defined herein, R^(C) is halogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, optionally substituted sulfonyl, —OR^(f),—SR^(f), —N(R^(f))₂, —NO₂, or —CN.

In certain embodiments, R^(C) is halogen. In certain embodiments, R^(C)is —F. In certain embodiments, R^(C) is —Cl, —^(C)r, or —I. In certainembodiments, R^(C) is —NO₂. In certain embodiments, R^(C) is —CN.

In certain embodiments, R^(C) is optionally substituted alkyl, e.g.,optionally substituted C₁₋₆ alkyl, optionally substituted C₁₋₂ alkyl,optionally substituted C₂₋₃ alkyl, optionally substituted C₃₋₄ alkyl,optionally substituted C₄₋₅ alkyl, or optionally substituted C₅₋₆ alkyl.In certain embodiments, R^(C) is unsubstituted alkyl, e.g.,unsubstituted C₁₋₆ alkyl, unsubstituted C₁₋₂ alkyl, unsubstituted C₂₋₃alkyl, unsubstituted C₃₋₄ alkyl, unsubstituted C₄₋₅ alkyl, orunsubstituted C₅₋₆ alkyl. In certain embodiments, R^(C) is methyl. Incertain embodiments, R^(C) is ethyl, propyl, or butyl. In certainembodiments, R^(C) is haloalkyl, e.g., —CHF₂, —CHCl₂, —CH₂CHF₂,—CH₂CHCl₂. In certain embodiments, R^(C) is perhaloalkyl, e.g., —CF₃,—CF₂CF₃, —CCl₃. In certain embodiments, R^(C) is hydroxyalkyl, e.g.,—CH₂OH, —CH₂CH₂OH, —CH₂OR^(f), —CH₂CH₂OR^(f). In certain embodiments,R^(C) is aminoalkyl, e.g., —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NMe₂, —CH₂CH₂NMe₂,—CH₂N(R^(f))₂, —CH₂CH₂N(R^(f))₂.

In certain embodiments, R^(C) is optionally substituted alkenyl, e.g.,optionally substituted C₂₋₆ alkenyl. In certain embodiments, R^(C) isunsubstituted alkenyl, e.g., unsubstituted C₂₋₆ alkenyl. In certainembodiments, R^(C) is vinyl, allyl, or prenyl. In certain embodiments,R^(C) is optionally substituted alkynyl, e.g., optionally substitutedC₂₋₆ alkynyl. In certain embodiments, R^(C) is unsubstituted alkynyl,e.g., unsubstituted C₂₋₆ alkynyl.

In certain embodiments, R^(C) is optionally substituted carbocyclyl,e.g., optionally substituted C₃₋₆ carbocyclyl, optionally substitutedC₃₋₄ carbocyclyl, optionally substituted C₄₋₅ carbocyclyl, or optionallysubstituted C₅₋₆ carbocyclyl. In certain embodiments, R^(C) isunsubstituted carbocyclyl, e.g., unsubstituted C₃₋₆ carbocyclyl. In someembodiments, R^(C) is cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl. In certain embodiments, R^(C) is optionally substitutedheterocyclyl, e.g., optionally substituted 3-6 membered heterocyclyl,optionally substituted 3-4 membered heterocyclyl, optionally substituted4-5 membered heterocyclyl, or optionally substituted 5-6 memberedheterocyclyl. In certain embodiments, R^(C) is unsubstitutedheterocyclyl, e.g., unsubstituted 3-6 membered heterocyclyl,unsubstituted 3-4 membered heterocyclyl, unsubstituted 4-5 memberedheterocyclyl, or unsubstituted 5-6 membered heterocyclyl.

In certain embodiments, R^(C) is optionally substituted aryl, e.g.,optionally substituted phenyl. In certain embodiments, R^(C) isunsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments,R^(C) is optionally substituted heteroaryl, e.g., optionally substituted5-6 membered heteroaryl, or optionally substituted 9-10 memberedbicyclic heteroaryl. In certain embodiments, R^(C) is unsubstitutedheteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, orunsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments,R^(C) is optionally substituted aralkyl, e.g., optionally substitutedbenzyl. In certain embodiments, R^(C) is optionally substitutedheteroaralkyl, e.g., methyl substituted with an optionally substituted5-6 membered heteroaryl ring. In certain embodiments, R^(C) isunsubstituted aralkyl, e.g., unsubstituted benzyl. In certainembodiments, R^(C) is unsubstituted heteroaralkyl, e.g., methylsubstituted with an unsubstituted 5-6 membered heteroaryl ring.

In certain embodiments, R^(C) is optionally substituted acyl, e.g.,—CHO, —CO₂H, or —C(═O)NH₂. In certain embodiments, R^(C) is —C(═O)R^(f),—C(═O)OR^(f), —C(═O)NH(R^(f)), or —C(═O)N(R^(f))₂. In certainembodiments, R^(C) is —C(═O)R^(f), and R^(f) is optionally substitutedalkyl, e.g., —C(═O)Me. In certain embodiments, R^(C) is —C(═O)R^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, R^(C)is —C(═O)R^(f), and R^(f) is optionally substituted carbocyclyl,heterocyclyl, aryl, or heteroaryl. In certain embodiments, R^(C) is—C(═O)OR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, R^(C) is —C(═O)OR^(f), and R^(f) is optionally substitutedalkenyl. In certain embodiments, R^(C) is —C(═O)OR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.In certain embodiments, R^(C) is —C(═O)N(R^(f))₂, and at least one R^(f)is optionally substituted alkyl. In certain embodiments, R^(C) is—C(═O)NHR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, R^(C) is —C(═O)NHR^(f), and R^(f) is optionally substitutedalkenyl. In certain embodiments, R^(C) is —C(═O)NHR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

In certain embodiments, R^(C) is optionally substituted sulfonyl, e.g.,—S(═O)₂OH. In certain embodiments, R^(C) is —S(═O)₂R^(f), —S(═O)₂OR^(f),—S(═O)₂NH(R^(f)), or —S(═O)₂N(R^(f))₂. In certain embodiments, R^(C) is—S(═O)₂R^(f), and R^(f) is optionally substituted alkyl, e.g.,—S(═O)₂Me. In certain embodiments, R^(C) is —S(═O)₂R^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.In certain embodiments, R^(C) is —S(═O)₂OR^(f), and R^(f) is optionallysubstituted alkyl. In certain embodiments, R^(C) is —S(═O)₂OR^(f), andR^(f) is optionally substituted aryl. In certain embodiments, R^(C) is—S(═O)₂N(R^(f))₂, and at least one R^(f) is optionally substitutedalkyl. In certain embodiments, R^(C) is —S(═O)₂NHR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

In certain embodiments, R^(C) is —OR^(f), e.g., —OH. In certainembodiments, R^(C) is —OR^(f), and R^(f) is optionally substitutedalkyl. In certain embodiments, R^(C) is —OR^(f), and R^(f) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(C) is —OR^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, R^(C)is —OR^(f), and R^(f) is optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl optionallysubstituted heteroaryl. In certain embodiments, R^(C) is —OR^(f), andR^(f) is unsubstituted carbocyclyl, unsubstituted heterocyclyl,unsubstituted aryl unsubstituted heteroaryl. In certain embodiments,R^(C) is —OR^(f), and R^(f) is optionally substituted acyl, e.g., R^(C)is —OC(═O)R^(f), —OC(═O)OR^(f), or —OC(═O)N(R^(f))₂. In certainembodiments, R^(C) is —OR^(f), and R^(f) is an oxygen protecting group.

In certain embodiments, R^(C) is —SR^(f), e.g., —SH. In certainembodiments, R^(C) is —SR^(f), and R^(f) is optionally substitutedalkyl. In certain embodiments, R^(C) is —SR^(f), and R^(f) isunsubstituted C₁₋₆ alkyl. In certain embodiments, R^(C) is —SR^(f), andR^(f) is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl optionally substitutedheteroaryl. In certain embodiments, R^(C) is —SR^(f), and R^(f) isunsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstitutedaryl unsubstituted heteroaryl. In certain embodiments, R^(C) is —SR^(f),and R^(f) is a sulfur protecting group.

In certain embodiments, R^(C) is —N(R^(f))₂, e.g., —NH₂, —NHR^(f). Incertain embodiments, R^(C) is —NH(R^(f)), and R^(f) is optionallysubstituted alkyl. In certain embodiments, R^(C) is —N(R^(f))₂, and atleast one R^(f) is optionally substituted alkyl. In certain embodiments,R^(C) is —NH(R^(f)), and R^(f) is unsubstituted alkyl. In certainembodiments, R^(C) is —N(R^(f))₂, and at least one R^(f) isunsubstituted alkyl. In certain embodiments, R^(C) is —NHR^(f), andR^(f) is optionally substituted carbocyclyl, optionally substitutedheterocyclyl, optionally substituted aryl, or optionally substitutedheteroaryl. In certain embodiments, R^(C) is —NHR^(f), and R^(f) isunsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstitutedaryl, or unsubstituted heteroaryl. In certain embodiments, R^(C) is—NHR^(f), and R^(f) is optionally substituted acyl, e.g., R^(C) is—NHC(═O)R^(f), —NHC(═O)OR^(f), or —NHC(═O)NHR^(f). In certainembodiments, R^(C) is —N(R^(f))₂, and at least one R^(f) is a nitrogenprotecting group. In certain embodiments, R^(C) is —N(R^(f))₂, and bothR^(f) are joined to form an optionally substituted heterocyclic oroptionally substituted heteroaryl ring. In certain embodiments, R^(C) is—N(R^(f))₂, and both R^(f) are joined to form an unsubstitutedheterocyclic or unsubstituted heteroaryl ring.

In certain embodiments, an R^(C) attached para to the diazepine ishalogen. In certain embodiments, an R^(C) attached para to the diazepineis —F. In certain embodiments, an Rc attached para to the diazepine is—Cl, —Br, or —I. In certain embodiments, an Rc attached para to thediazepine is —NO₂. In certain embodiments, an R^(C) attached para to thediazepine is —CN.

In certain embodiments, an R^(C) attached para to the diazepine isoptionally substituted alkyl, e.g., optionally substituted C₁₋₆ alkyl,optionally substituted C₁₋₂ alkyl, optionally substituted C₂₋₃ alkyl,optionally substituted C₃₋₄ alkyl, optionally substituted C₄₋₅ alkyl, oroptionally substituted C₅₋₆ alkyl. In certain embodiments, an R^(C)attached para to the diazepine is unsubstituted alkyl, e.g.,unsubstituted C₁₋₆ alkyl, unsubstituted C₁₋₂ alkyl, unsubstituted C₂₋₃alkyl, unsubstituted C₃₋₄ alkyl, unsubstituted C₄₋₅ alkyl, orunsubstituted C₅₋₆ alkyl. In certain embodiments, an R^(C) attached parato the diazepine is methyl. In certain embodiments, an R^(C) attachedpara to the diazepine is ethyl, propyl, or butyl. In certainembodiments, an R^(C) attached para to the diazepine is haloalkyl, e.g.,—CHF₂, —CHCl₂, —CH₂CHF₂, —CH₂CHCl₂. In certain embodiments, an R^(C)attached para to the diazepine is perhaloalkyl, e.g., —CF₃, —CF₂CF₃,—CCl₃. In certain embodiments, an R^(C) attached para to the diazepineis hydroxyalkyl, e.g., —CH₂OH, —CH₂CH₂OH, —CH₂OR^(f), —CH₂CH₂OR^(f). Incertain embodiments, an R^(C) attached para to the diazepine isaminoalkyl, e.g., —CH₂NH₂, —CH₂CH₂NH₂, —CH₂NMe₂, —CH₂CH₂NMe₂,—CH₂N(R^(f))₂, —CH₂CH₂N(R^(f))₂.

In certain embodiments, an R^(C) attached para to the diazepine isoptionally substituted alkenyl, e.g., optionally substituted C₂₋₆alkenyl. In certain embodiments, an Rc attached para to the diazepine isunsubstituted alkenyl, e.g., unsubstituted C₂₋₆ alkenyl. In certainembodiments, an R^(C) attached para to the diazepine is vinyl, allyl, orprenyl. In certain embodiments, an R^(C) attached para to the diazepineis optionally substituted alkynyl, e.g., optionally substituted C₂₋₆alkynyl. In certain embodiments, an R^(C) attached para to the diazepineis unsubstituted alkynyl, e.g., unsubstituted C₂₋₆ alkynyl.

In certain embodiments, an R^(C) attached para to the diazepine isoptionally substituted carbocyclyl, e.g., optionally substituted C₃₋₆carbocyclyl, optionally substituted C₃₋₄ carbocyclyl, optionallysubstituted C₄₋₅ carbocyclyl, or optionally substituted C₅₋₆carbocyclyl. In certain embodiments, an R^(C) attached para to thediazepine is unsubstituted carbocyclyl, e.g., unsubstituted C₃₋₆carbocyclyl. In some embodiments, an R^(C) attached para to thediazepine is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. Incertain embodiments, an R^(C) attached para to the diazepine isoptionally substituted heterocyclyl, e.g., optionally substituted 3-6membered heterocyclyl, optionally substituted 3-4 membered heterocyclyl,optionally substituted 4-5 membered heterocyclyl, or optionallysubstituted 5-6 membered heterocyclyl. In certain embodiments, an R^(C)attached para to the diazepine is unsubstituted heterocyclyl, e.g.,unsubstituted 3-6 membered heterocyclyl, unsubstituted 3-4 memberedheterocyclyl, unsubstituted 4-5 membered heterocyclyl, or unsubstituted5-6 membered heterocyclyl.

In certain embodiments, an R^(C) attached para to the diazepine isoptionally substituted aryl, e.g., optionally substituted phenyl. Incertain embodiments, an R^(C) attached para to the diazepine isunsubstituted aryl, e.g., unsubstituted phenyl. In certain embodiments,an R^(C) attached para to the diazepine is optionally substitutedheteroaryl, e.g., optionally substituted 5-6 membered heteroaryl, oroptionally substituted 9-10 membered bicyclic heteroaryl. In certainembodiments, an R^(C) attached para to the diazepine is unsubstitutedheteroaryl, e.g., unsubstituted 5-6 membered heteroaryl, orunsubstituted 9-10 membered bicyclic heteroaryl. In certain embodiments,an R^(C) attached para to the diazepine is optionally substitutedaralkyl, e.g., optionally substituted benzyl. In certain embodiments, anR^(C) attached para to the diazepine is optionally substitutedheteroaralkyl, e.g., methyl substituted with an optionally substituted5-6 membered heteroaryl ring. In certain embodiments, an R^(C) attachedpara to the diazepine is unsubstituted aralkyl, e.g., unsubstitutedbenzyl. In certain embodiments, an R^(C) attached para to the diazepineis unsubstituted heteroaralkyl, e.g., methyl substituted with anunsubstituted 5-6 membered heteroaryl ring.

In certain embodiments, an R^(C) attached para to the diazepine isoptionally substituted acyl, e.g., —CHO, —CO₂H, or —C(═O)NH₂. In certainembodiments, an Rc attached para to the diazepine is —C(═O)R^(f),—C(═O)OR^(f), —C(═O)NH(R^(f)), or —C(═O)N(R^(f))₂. In certainembodiments, an R^(C) attached para to the diazepine is —C(═O)R^(f), andR^(f) is optionally substituted alkyl, e.g., —C(═O)Me. In certainembodiments, an R^(C) attached para to the diazepine is —C(═O)R^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, anR^(C) attached para to the diazepine is —C(═O)R^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.In certain embodiments, an R^(C) attached para to the diazepine is—C(═O)OR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, an R^(C) attached para to the diazepine is —C(═O)OR^(f),and R^(f) is optionally substituted alkenyl. In certain embodiments, anR^(C) attached para to the diazepine is —C(═O)OR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.In certain embodiments, an R^(C) attached para to the diazepine is—C(═O)N(R^(f))₂, and at least one R^(f) is optionally substituted alkyl.In certain embodiments, an R^(C) attached para to the diazepine is—C(═O)NHR^(f), and R^(f) is optionally substituted alkyl. In certainembodiments, an Rc attached para to the diazepine is —C(═O)NHR^(f), andR^(f) is optionally substituted alkenyl. In certain embodiments, anR^(C) attached para to the diazepine is —C(═O)NHR^(f), and R^(f) isoptionally substituted carbocyclyl, heterocyclyl, aryl, or heteroaryl.

In certain embodiments, an R^(C) attached para to the diazepine is—OR^(f), e.g., —OH. In certain embodiments, an R^(C) attached para tothe diazepine is —OR^(f), and R^(f) is optionally substituted alkyl. Incertain embodiments, an R^(C) attached para to the diazepine is —OR^(f),and R^(f) is unsubstituted C₁₋₆ alkyl. In certain embodiments, an R^(C)attached para to the diazepine is —OR^(f), and R^(f) is optionallysubstituted alkenyl. In certain embodiments, an R^(C) attached para tothe diazepine is —OR^(f), and R^(f) is optionally substitutedcarbocyclyl, optionally substituted heterocyclyl, optionally substitutedaryl optionally substituted heteroaryl. In certain embodiments, an R^(C)attached para to the diazepine is —OR^(f), and R^(f) is unsubstitutedcarbocyclyl, unsubstituted heterocyclyl, unsubstituted arylunsubstituted heteroaryl. In certain embodiments, an R^(C) attached parato the diazepine is —OR^(f), and R^(f) is optionally substituted acyl,e.g., an R^(C) attached para to the diazepine is —OC(═O)R^(f),—OC(═O)OR^(f), or —OC(═O)N(R^(f))₂. In certain embodiments, an R^(C)attached para to the diazepine is —OR^(f), and R^(f) is an oxygenprotecting group.

In certain embodiments, an R^(C) attached para to the diazepine isoptionally substituted sulfonyl, e.g., —S(═O)₂OH. In certainembodiments, an R^(C) attached para to the diazepine is —S(═O)₂R^(f),—S(═O)₂OR^(f), —S(═O)₂NH(R^(f)), or —S(═O)₂N(R^(f))₂. In certainembodiments, an R^(C) attached para to the diazepine is —S(═O)₂R^(f),and R^(f) is optionally substituted alkyl, e.g., —S(═O)₂Me. In certainembodiments, an R^(C) attached para to the diazepine is —S(═O)₂R^(f),and R^(f) is optionally substituted carbocyclyl, heterocyclyl, aryl, orheteroaryl. In certain embodiments, an R^(C) attached para to thediazepine is —S(═O)₂OR^(f), and R^(f) is optionally substituted alkyl.In certain embodiments, an R^(C) attached para to the diazepine is—S(═O)₂OR^(f), and R^(f) is optionally substituted aryl. In certainembodiments, an Rc attached para to the diazepine is —S(═O)₂N(R^(f))₂,and at least one R^(f) is optionally substituted alkyl. In certainembodiments, an R^(C) attached para to the diazepine is —S(═O)₂NHR^(f),and R^(f) is optionally substituted carbocyclyl, heterocyclyl, aryl, orheteroaryl.

In certain embodiments, an R^(C) attached para to the diazepine is—SR^(f), e.g., —SH. In certain embodiments, an R^(C) attached para tothe diazepine is —SR^(f), and R^(f) is optionally substituted alkyl. Incertain embodiments, an R^(C) attached para to the diazepine is —SR^(f),and R^(f) is unsubstituted C₁₋₆ alkyl. In certain embodiments, an R^(C)attached para to the diazepine is —SR^(f), and R^(f) is optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl optionally substituted heteroaryl. In certainembodiments, an Rc attached para to the diazepine is —SR^(f), and R^(f)is unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstitutedaryl unsubstituted heteroaryl. In certain embodiments, an Rc attachedpara to the diazepine is —SR^(f), and R^(f) is a sulfur protectinggroup.

In certain embodiments, an R^(C) attached para to the diazepine is—N(R^(f))₂, e.g., —NH₂, —NHR^(f). In certain embodiments, an R^(C)attached para to the diazepine is —NH(R^(f)), and R^(f) is optionallysubstituted alkyl. In certain embodiments, an R^(C) attached para to thediazepine is —N(R^(f))₂, and at least one R^(f) is optionallysubstituted alkyl. In certain embodiments, an Rc attached para to thediazepine is —NH(R^(f)), and R^(f) is unsubstituted alkyl. In certainembodiments, an R^(C) attached para to the diazepine is —N(R^(f))₂, andat least one R^(f) is unsubstituted alkyl. In certain embodiments, anR^(C) attached para to the diazepine is —NHR^(f), and R^(f) isoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl. Incertain embodiments, an Rc attached para to the diazepine is —NHR^(f),and R^(f) is unsubstituted carbocyclyl, unsubstituted heterocyclyl,unsubstituted aryl, or unsubstituted heteroaryl. In certain embodiments,an Rc attached para to the diazepine is —NHR^(f), and R^(f) isoptionally substituted acyl, e.g., an Rc attached para to the diazepineis —NHC(═O)R^(f), —NHC(═O)OR^(f), or —NHC(═O)NHR^(f). In certainembodiments, an R^(C) attached para to the diazepine is —N(R^(f))₂, andat least one R^(f) is a nitrogen protecting group. In certainembodiments, an R^(C) attached para to the diazepine is —N(R^(f))₂, andboth R^(f) are joined to form an optionally substituted heterocyclic oroptionally substituted heteroaryl ring. In certain embodiments, an R^(C)attached para to the diazepine is —N(R^(f))₂, and both R^(f) are joinedto form an unsubstituted heterocyclic or unsubstituted heteroaryl ring.

In certain embodiments, the compound of Formula (I) is a compound listedin Table 1.

TABLE I Exemplary compounds of Formula (I)

501

502

503

504

505

In certain embodiments, the compound of Formula (I) is a compound listedin Table 2.

TABLE 2 Exemplary compounds of Formula (I)

601

602

603

604

605

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-A-1):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-A-2):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-B-1):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-B-2):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-B-3):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-B-4):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-1):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-2):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-3):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-4):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-5):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-6):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-7):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-8):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-9):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-10):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-11):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-C-12):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-D-1):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-D-2):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-D-3):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-D-4):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-D-5):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-D-6):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-D-7):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-D-8):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-E-1):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-E-2):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-E-3):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-E-4):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-E-5):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-E-6):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-E-7):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, the compound of Formula (I) is a compound ofFormula (I-E-8):

or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate,hydrate, polymorph, co-crystal, or prodrug thereof.

In certain embodiments, a compound of Formula (I) has improved metabolicstability relative to a known bromodomain inhibitor (e.g., JQ1). Incertain embodiments, a compound of Formula (I) has decreasedlipophilicity relative to a known bromodomain inhibitor (e.g., JQ1). Incertain embodiments, a compound of Formula (I) has improvedpharmacokinetic parameters relative to a known bromodomain inhibitor(e.g., JQ1). In some embodiments, the compound has a higher clearance.In some embodiments, the compound has a lower clearance. In someembodiments, the compound has a higher volume distribution (e.g.,steady-state volume distribution). In some embodiments, the compound hasa lower volume distribution (e.g., steady-state volume distribution). Insome embodiments, the compound has a longer half-life (e.g., terminalt_(1/2)). In some embodiments, the compound has a lower half-life (e.g.,terminal t_(1/2)). In some embodiments, the compound has a higherintegral area under the concentration-time curve (e.g., AUC_(last),AUC_(0-∞)). In some embodiments, the compound has a lower integral areaunder the concentration-time curve (e.g., AUC_(last), AUC_(0-∞)). Insome embodiments, the compound has a higher time to maximumconcentration. In some embodiments, the compound has a lower time tomaximum concentration. In some embodiments, the compound has a highermaximum concentration (e.g., maximum plasma concentration). In someembodiments, the compound has a lower maximum concentration (e.g.,maximum plasma concentration). In some embodiments, the compound has ahigher bioavailability. In some embodiments, the compound has a lowerbioavailability.

Pharmaceutical Compositions and Administration

The present disclosure provides pharmaceutical compositions comprising acompound described herein (e.g., a compound of Formula (I)), or apharmaceutically acceptable salt, solvate, hydrate, polymorph,co-crystal, tautomer, stereoisomer, isotopically labeled derivative, orprodrug thereof), and optionally a pharmaceutically acceptableexcipient. In certain embodiments, the pharmaceutical compositiondescribed herein comprises a compound of Formula (I), or apharmaceutically acceptable salt thereof, and optionally apharmaceutically acceptable excipient. In certain embodiments, thepharmaceutical composition described herein comprises a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable excipient.

In certain embodiments, the compound described herein is provided in aneffective amount in the pharmaceutical composition. In certainembodiments, the effective amount is a therapeutically effective amount.In certain embodiments, the effective amount is a prophylacticallyeffective amount. In certain embodiments, the effective amount is anamount effective for treating and/or preventing a disease (e.g., adisease described herein) in a subject in need thereof. In certainembodiments, the effective amount is an amount effective for treating adisease in a subject in need thereof. In certain embodiments, theeffective amount is an amount effective for preventing a disease in asubject in need thereof. In certain embodiments, the effective amount isan amount effective for reducing the risk of developing a disease in asubject in need thereof. In certain embodiments, the effective amount isan amount effective for male contraception (e.g., effective forinhibiting sperm formation) in a subject in need thereof. In certainembodiments, the effective amount is an amount effective for inhibitingthe replication of a virus. In certain embodiments, the effective amountis an amount effective for killing a virus. In certain embodiments, theeffective amount is an amount effective for inhibiting the activity(e.g., aberrant activity, such as increased activity) of abromodomain-containing protein in a subject or cell. In certainembodiments, the effective amount is an amount effective for inhibitingthe activity (e.g., aberrant activity, such as increased activity) of abromodomain in a subject or cell. In certain embodiments, the effectiveamount is an amount effective for inhibiting the binding of abromodomain of a bromodomain-containing protein to an acetyl-lysineresidue of a second protein (e.g., a histone) in a subject or cell. Incertain embodiments, the effective amount is an amount effective formodulating (e.g., inhibiting) transcriptional elongation in a subject orcell. In certain embodiments, the effective amount is an amounteffective for modulating (e.g., down-regulating or inhibiting) theexpression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein in a subject or cell. In certainembodiments, the effective amount is an amount effective for inducingapoptosis of a cell. In certain embodiments, the effective amount is anamount effective for inducing apoptosis in a subject. In certainembodiments, the effective amount is an amount effective for inducing G1arrest in a subject or cell. An effective amount of a compound may varyfrom about 0.001 mg/kg to about 1000 mg/kg in one or more doseadministrations for one or several days (depending on the mode ofadministration). In certain embodiments, the effective amount per dosevaries from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kgto about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150mg/kg.

In certain embodiments, the effective amount is an amount effective forinhibiting the activity of a bromodomain-containing protein, theactivity of a bromodomain, the binding of a bromodomain of abromodomain-containing protein to an acetyl-lysine residue of a secondprotein (e.g., a histone), the transcriptional elongation, and/or theexpression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein, for inducing or increasing apoptosis, orfor inducing or increasing G1 arrest by at least about 10%, at leastabout 20%, at least about 30%, at least about 40%, at least about 50%,at least about 60%, at least about 70%, at least about 80%, at leastabout 90%, at least about 95%, or at least about 98%. In certainembodiments, the effective amount is an amount effective for inhibitingthe activity of a bromodomain-containing protein, the binding of abromodomain of a bromodomain-containing protein to an acetyl-lysineresidue of a second protein (e.g., a histone), and/or the expression(e.g., transcription) of a gene that is regulated by abromodomain-containing protein by at most about 90%, at most about 80%,at most about 70%, at most about 60%, at most about 50%, at most about40%, at most about 30%, at most about 20%, or at most about 10%.Combinations of the ranges described herein (e.g., at least about 20%and at most about 50%) are also within the scope of the disclosure. Incertain embodiments, the activity of a bromodomain-containing protein,the binding of a bromodomain of a bromodomain-containing protein to anacetyl-lysine residue of a second protein (e.g., a histone), and/or theexpression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein are inhibited by a percentage or a rangeof percentage described herein by an effective amount of a compounddescribed herein.

In certain embodiments, the gene regulated by a bromodomain-containingprotein is a gene regulated by a bromo and extra terminal protein (BET).In certain embodiments, the gene regulated by a bromodomain-containingprotein is BRD2. In certain embodiments, the gene regulated by abromodomain-containing protein is BRD2(1). In certain embodiments, thegene regulated by a bromodomain-containing protein is BRD2(2). Incertain embodiments, the gene regulated by a bromodomain-containingprotein is BRD3. In certain embodiments, the gene regulated by abromodomain-containing protein is BRD3(1). In certain embodiments, thegene regulated by a bromodomain-containing protein is BRD3(2). Incertain embodiments, the gene regulated by a bromodomain-containingprotein is BRD4. In certain embodiments, the gene regulated by abromodomain-containing protein is BRD4(1). In certain embodiments, thegene regulated by a bromodomain-containing protein is BRD4(2). Incertain embodiments, the gene regulated by a bromodomain-containingprotein is BRDT. In certain embodiments, the gene regulated by abromodomain-containing protein is BRDT(1). In certain embodiments, thegene regulated by a bromodomain-containing protein is BRDT(2). Incertain embodiments, the gene regulated by a bromodomain-containingprotein is a gene regulated by a TBP (TATA box bindingprotein)-associated factor protein (TAF). In certain embodiments, thegene regulated by a bromodomain-containing protein is TAF1. In certainembodiments, the gene regulated by a bromodomain-containing protein isTAF1L. In certain embodiments, the gene regulated by abromodomain-containing protein is a gene regulated by a CREB-bindingprotein (CBP). In certain embodiments, the gene regulated by abromodomain-containing protein is a gene regulated by an E1A bindingprotein p300 (EP300).

Pharmaceutical compositions described herein can be prepared by anymethod known in the art of pharmacology. In general, such preparatorymethods include the steps of bringing the compound described herein(i.e., the “active ingredient”) into association with a carrier orexcipient, and/or one or more other accessory ingredients, and then, ifnecessary and/or desirable, shaping, and/or packaging the product into adesired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold inbulk, as a single unit dose, and/or as a plurality of single unit doses.A “unit dose” is a discrete amount of the pharmaceutical compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient which would be administered to a subject and/or a convenientfraction of such a dosage such as, for example, one-half or one-third ofsuch a dosage.

Relative amounts of the active ingredient, the pharmaceuticallyacceptable excipient, and/or any additional ingredients in apharmaceutical composition described herein will vary, depending uponthe identity, size, and/or condition of the subject treated and furtherdepending upon the route by which the composition is to be administered.The composition may comprise between 0.1% and 100% (w/w) activeingredient.

Pharmaceutically acceptable excipients used in the manufacture ofprovided pharmaceutical compositions include inert diluents, dispersingand/or granulating agents, surface active agents and/or emulsifiers,disintegrating agents, binding agents, preservatives, buffering agents,lubricating agents, and/or oils. Excipients such as cocoa butter andsuppository waxes, coloring agents, coating agents, sweetening,flavoring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogenphosphate, sodium phosphate lactose, sucrose, cellulose,microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodiumchloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch,corn starch, tapioca starch, sodium starch glycolate, clays, alginicacid, guar gum, citrus pulp, agar, bentonite, cellulose, and woodproducts, natural sponge, cation-exchange resins, calcium carbonate,silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone)(crospovidone), sodium carboxymethyl starch (sodium starch glycolate),carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose(croscarmellose), methylcellulose, pregelatinized starch (starch 1500),microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate,quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include naturalemulsifiers (e.g., acacia, agar, alginic acid, sodium alginate,tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk,casein, wool fat, cholesterol, wax, and lecithin), colloidal clays(e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminumsilicate)), long chain amino acid derivatives, high molecular weightalcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetinmonostearate, ethylene glycol distearate, glyceryl monostearate, andpropylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.,carboxy polymethylene, polyacrylic acid, acrylic acid polymer, andcarboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.,carboxymethylcellulose sodium, powdered cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylenesorbitan monolaurate (Tween® 20), polyoxyethylene sorbitan (Tween® 60),polyoxyethylene sorbitan monooleate (Tween® 80), sorbitan monopalmitate(Span® 40), sorbitan monostearate (Span® 60), sorbitan tristearate(Span® 65), glyceryl monooleate, sorbitan monooleate (Span® 80),polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj® 45),polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil,polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters,polyethylene glycol fatty acid esters (e.g., Cremophor®),polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij® 30)),poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamineoleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium lauryl sulfate, Pluronic® F-68, Poloxamer P-188,cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride,docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g., cornstarch and starchpaste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin,molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums(e.g., acacia, sodium alginate, extract of Irish moss, panwar gum,ghatti gum, mucilage of isapol husks, carboxymethylcellulose,methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, microcrystalline cellulose,cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate(Veegum®), and larch arabogalactan), alginates, polyethylene oxide,polyethylene glycol, inorganic calcium salts, silicic acid,polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents,antimicrobial preservatives, antifungal preservatives, antiprotozoanpreservatives, alcohol preservatives, acidic preservatives, and otherpreservatives. In certain embodiments, the preservative is anantioxidant. In other embodiments, the preservative is a chelatingagent.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, potassium metabisulfite, propionic acid, propylgallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, andsodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid(EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodiumedetate, trisodium edetate, calcium disodium edetate, dipotassiumedetate, and the like), citric acid and salts and hydrates thereof(e.g., citric acid monohydrate), fumaric acid and salts and hydratesthereof, malic acid and salts and hydrates thereof, phosphoric acid andsalts and hydrates thereof, and tartaric acid and salts and hydratesthereof. Exemplary antimicrobial preservatives include benzalkoniumchloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide,cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol,chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea,phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate,propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methylparaben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoicacid, potassium benzoate, potassium sorbate, sodium benzoate, sodiumpropionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol,phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate,and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E,beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbicacid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylatedhydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS),sodium lauryl ether sulfate (SLES), sodium bisulfite, sodiummetabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall® 115, Germaben® II, Neolone®,Kathon®, and Euxyl®.

Exemplary buffering agents include citrate buffer solutions, acetatebuffer solutions, phosphate buffer solutions, ammonium chloride, calciumcarbonate, calcium chloride, calcium citrate, calcium glubionate,calcium gluceptate, calcium gluconate, D-gluconic acid, calciumglycerophosphate, calcium lactate, propanoic acid, calcium levulinate,pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasiccalcium phosphate, calcium hydroxide phosphate, potassium acetate,potassium chloride, potassium gluconate, potassium mixtures, dibasicpotassium phosphate, monobasic potassium phosphate, potassium phosphatemixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodiumcitrate, sodium lactate, dibasic sodium phosphate, monobasic sodiumphosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide,aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline,Ringer's solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calciumstearate, stearic acid, silica, talc, malt, glyceryl behanate,hydrogenated vegetable oils, polyethylene glycol, sodium benzoate,sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate,sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway,carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee,corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed,geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate,jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademianut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, andwheat germ oils. Exemplary synthetic oils include, but are not limitedto, butyl stearate, caprylic triglyceride, capric triglyceride,cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate,mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixturesthereof.

Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active ingredients,the liquid dosage forms may comprise inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed,groundnut, corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof. Besides inert diluents, the oralcompositions can include adjuvants such as wetting agents, emulsifyingand suspending agents, sweetening, flavoring, and perfuming agents. Incertain embodiments for parenteral administration, the conjugatesdescribed herein are mixed with solubilizing agents such as Cremophor®,alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins,polymers, and mixtures thereof.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation can be a sterile injectable solution,suspension, or emulsion in a nontoxic parenterally acceptable diluent orsolvent, for example, as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P., and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or di-glycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This can be accomplished by the use of a liquid suspension ofcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolution,which, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform may be accomplished by dissolving or suspending the drug in an oilvehicle.

Compositions for rectal or vaginal administration are typicallysuppositories which can be prepared by mixing the conjugates describedherein with suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol, or a suppository wax which are solid atambient temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active ingredient.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activeingredient is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or (a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, (b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, (c) humectants such as glycerol, (d) disintegratingagents such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, (e) solutionretarding agents such as paraffin, (f) absorption accelerators such asquaternary ammonium compounds, (g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolinand bentonite clay, and (i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets, and pills, thedosage form may include a buffering agent.

Solid compositions of a similar type can be employed as fillers in softand hard-filled gelatin capsules using such excipients as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike. The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the art of pharmacology. Theymay optionally comprise opacifying agents and can be of a compositionthat they release the active ingredient(s) only, or preferentially, in acertain part of the intestinal tract, optionally, in a delayed manner.Examples of encapsulating compositions which can be used includepolymeric substances and waxes. Solid compositions of a similar type canbe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

The active ingredient can be in a micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings, and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active ingredient can be admixed with at least oneinert diluent such as sucrose, lactose, or starch. Such dosage forms maycomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may comprise bufferingagents. They may optionally comprise opacifying agents and can be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of encapsulating agents which can be usedinclude polymeric substances and waxes.

Dosage forms for topical and/or transdermal administration of a compounddescribed herein may include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants, and/or patches. Generally, theactive ingredient is admixed under sterile conditions with apharmaceutically acceptable carrier or excipient and/or any neededpreservatives and/or buffers as can be required. Additionally, thepresent disclosure contemplates the use of transdermal patches, whichoften have the added advantage of providing controlled delivery of anactive ingredient to the body. Such dosage forms can be prepared, forexample, by dissolving and/or dispensing the active ingredient in theproper medium. Alternatively or additionally, the rate can be controlledby either providing a rate controlling membrane and/or by dispersing theactive ingredient in a polymer matrix and/or gel.

Intradermal compositions can be administered by devices which limit theeffective penetration length of a needle into the skin. Alternatively oradditionally, conventional syringes can be used in the classical mantouxmethod of intradermal administration. Jet injection devices whichdeliver liquid formulations to the dermis via a liquid jet injectorand/or via a needle which pierces the stratum corneum and produces a jetwhich reaches the dermis are suitable. Ballistic powder/particledelivery devices which use compressed gas to accelerate the compound inpowder form through the outer layers of the skin to the dermis aresuitable.

Formulations suitable for topical administration include, but are notlimited to, liquid and/or semi-liquid preparations such as liniments,lotions, oil-in-water and/or water-in-oil emulsions such as creams,ointments, and/or pastes, and/or solutions and/or suspensions. Topicallyadministrable formulations may, for example, comprise from about 1% toabout 10% (w/w) active ingredient, although the concentration of theactive ingredient can be as high as the solubility limit of the activeingredient in the solvent. Formulations for topical administration mayfurther comprise one or more of the additional ingredients describedherein.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation suitable for pulmonary administration viathe buccal cavity. Such a formulation may comprise dry particles whichcomprise the active ingredient and which have a diameter in the rangefrom about 0.5 to about 7 nanometers, or from about 1 to about 6nanometers. Such compositions are conveniently in the form of drypowders for administration using a device comprising a dry powderreservoir to which a stream of propellant can be directed to dispersethe powder and/or using a self-propelling solvent/powder dispensingcontainer such as a device comprising the active ingredient dissolvedand/or suspended in a low-boiling propellant in a sealed container. Suchpowders comprise particles wherein at least 98% of the particles byweight have a diameter greater than 0.5 nanometers and at least 95% ofthe particles by number have a diameter less than 7 nanometers.Alternatively, at least 95% of the particles by weight have a diametergreater than 1 nanometer and at least 90% of the particles by numberhave a diameter less than 6 nanometers. Dry powder compositions mayinclude a solid fine powder diluent such as sugar and are convenientlyprovided in a unit dose form.

Low boiling propellants generally include liquid propellants having aboiling point of below 65° F. at atmospheric pressure. Generally thepropellant may constitute 50 to 99.9% (w/w) of the composition, and theactive ingredient may constitute 0.1 to 20% (w/w) of the composition.The propellant may further comprise additional ingredients such as aliquid non-ionic and/or solid anionic surfactant and/or a solid diluent(which may have a particle size of the same order as particlescomprising the active ingredient).

Pharmaceutical compositions described herein formulated for pulmonarydelivery may provide the active ingredient in the form of droplets of asolution and/or suspension. Such formulations can be prepared, packaged,and/or sold as aqueous and/or dilute alcoholic solutions and/orsuspensions, optionally sterile, comprising the active ingredient, andmay conveniently be administered using any nebulization and/oratomization device. Such formulations may further comprise one or moreadditional ingredients including, but not limited to, a flavoring agentsuch as saccharin sodium, a volatile oil, a buffering agent, a surfaceactive agent, and/or a preservative such as methylhydroxybenzoate. Thedroplets provided by this route of administration may have an averagediameter in the range from about 0.1 to about 200 nanometers.

Formulations described herein as being useful for pulmonary delivery areuseful for intranasal delivery of a pharmaceutical composition describedherein. Another formulation suitable for intranasal administration is acoarse powder comprising the active ingredient and having an averageparticle from about 0.2 to 500 micrometers. Such a formulation isadministered by rapid inhalation through the nasal passage from acontainer of the powder held close to the nares.

Formulations for nasal administration may, for example, comprise fromabout as little as 0.1% (w/w) to as much as 100% (w/w) of the activeingredient, and may comprise one or more of the additional ingredientsdescribed herein. A pharmaceutical composition described herein can beprepared, packaged, and/or sold in a formulation for buccaladministration. Such formulations may, for example, be in the form oftablets and/or lozenges made using conventional methods, and maycontain, for example, 0.1 to 20% (w/w) active ingredient, the balancecomprising an orally dissolvable and/or degradable composition and,optionally, one or more of the additional ingredients described herein.Alternately, formulations for buccal administration may comprise apowder and/or an aerosolized and/or atomized solution and/or suspensioncomprising the active ingredient. Such powdered, aerosolized, and/oraerosolized formulations, when dispersed, may have an average particleand/or droplet size in the range from about 0.1 to about 200 nanometers,and may further comprise one or more of the additional ingredientsdescribed herein.

A pharmaceutical composition described herein can be prepared, packaged,and/or sold in a formulation for ophthalmic administration. Suchformulations may, for example, be in the form of eye drops including,for example, be in the form of eye drops including, for example, a 0.1-a0.1/1.0% (w/w) solution and/or suspension of the active ingredient in anaqueous or oily liquid carrier or excipient. Such drops may furthercomprise buffering agents, salts, and/or one or more other of theadditional ingredients described herein. Otheropthalmically-administrable formulations which are useful include thosewhich comprise the active ingredient in microcrystalline form and/or ina liposomal preparation. Ear drops and/or eye drops are alsocontemplated as being within the scope of this disclosure.

Although the descriptions of pharmaceutical compositions provided hereinare principally directed to pharmaceutical compositions which aresuitable for administration to humans, it will be understood by theskilled artisan that such compositions are generally suitable foradministration to animals of all sorts. Modification of pharmaceuticalcompositions suitable for administration to humans in order to renderthe compositions suitable for administration to various animals is wellunderstood, and the ordinarily skilled veterinary pharmacologist candesign and/or perform such modification with ordinary experimentation.

Compounds provided herein are typically formulated in dosage unit formfor ease of administration and uniformity of dosage. It will beunderstood, however, that the total daily usage of the compositionsdescribed herein will be decided by a physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular subject or organism will depend upon a varietyof factors including the disease being treated and the severity of thedisorder; the activity of the specific active ingredient employed; thespecific composition employed; the age, body weight, general health,sex, and diet of the subject; the time of administration, route ofadministration, and rate of excretion of the specific active ingredientemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific active ingredient employed; and likefactors well known in the medical arts.

The compounds and compositions provided herein can be administered byany route, including enteral (e.g., oral), parenteral, intravenous,intramuscular, intra-arterial, intramedullary, intrathecal,subcutaneous, intraventricular, transdermal, intradermal, rectal,intravaginal, intraperitoneal, topical (as by powders, ointments,creams, and/or drops), mucosal, nasal, bucal, sublingual; byintratracheal instillation, bronchial instillation, and/or inhalation;and/or as an oral spray, nasal spray, and/or aerosol. Specificallycontemplated routes are oral administration, intravenous administration(e.g., systemic intravenous injection), regional administration viablood and/or lymph supply, and/or direct administration to an affectedsite. In general, the most appropriate route of administration willdepend upon a variety of factors including the nature of the agent(e.g., its stability in the environment of the gastrointestinal tract),and/or the condition of the subject (e.g., whether the subject is ableto tolerate oral administration). In certain embodiments, the compoundor pharmaceutical composition described herein is suitable for topicaladministration to the eye of a subject.

The exact amount of a compound required to achieve an effective amountwill vary from subject to subject, depending, for example, on species,age, and general condition of a subject, severity of the side effects ordisorder, identity of the particular compound, mode of administration,and the like. The desired dosage can be delivered three times a day, twotimes a day, once a day, every other day, every third day, every week,every two weeks, every three weeks, or every four weeks. In certainembodiments, the desired dosage can be delivered using multipleadministrations (e.g., two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or more administrations). Aneffective amount may be included in a single dose (e.g., single oraldose) or multiple doses (e.g., multiple oral doses). In certainembodiments, when multiple doses are administered to a subject orapplied to a tissue or cell, any two doses of the multiple doses includedifferent or substantially the same amounts of a compound describedherein. In certain embodiments, when multiple doses are administered toa subject or applied to a tissue or cell, the frequency of administeringthe multiple doses to the subject or applying the multiple doses to thetissue or cell is three doses a day, two doses a day, one dose a day,one dose every other day, one dose every third day, one dose every week,one dose every two weeks, one dose every three weeks, or one dose everyfour weeks. In certain embodiments, the frequency of administering themultiple doses to the subject or applying the multiple doses to thetissue or cell is one dose per day. In certain embodiments, thefrequency of administering the multiple doses to the subject or applyingthe multiple doses to the tissue or cell is two doses per day. Incertain embodiments, the frequency of administering the multiple dosesto the subject or applying the multiple doses to the tissue or cell isthree doses per day. In certain embodiments, when multiple doses areadministered to a subject or applied to a tissue or cell, the durationbetween the first dose and last dose of the multiple doses is one day,two days, four days, one week, two weeks, three weeks, one month, twomonths, three months, four months, six months, nine months, one year,two years, three years, four years, five years, seven years, ten years,fifteen years, twenty years, or the lifetime of the subject, tissue, orcell. In certain embodiments, the duration between the first dose andlast dose of the multiple doses is three months, six months, or oneyear. In certain embodiments, the duration between the first dose andlast dose of the multiple doses is the lifetime of the subject, tissue,or cell. In certain embodiments, a dose (e.g., a single dose, or anydose of multiple doses) described herein includes independently between0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mgand 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g,inclusive, of a compound described herein. In certain embodiments, adose described herein includes independently between 1 mg and 3 mg,inclusive, of a compound described herein. In certain embodiments, adose described herein includes independently between 3 mg and 10 mg,inclusive, of a compound described herein. In certain embodiments, adose described herein includes independently between 10 mg and 30 mg,inclusive, of a compound described herein. In certain embodiments, adose described herein includes independently between 30 mg and 100 mg,inclusive, of a compound described herein.

In certain embodiments, an effective amount of a compound foradministration one or more times a day to a 70 kg adult human maycomprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg,about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosageform.

In certain embodiments, the compounds described herein may be at dosagelevels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg,from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kgto about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg,from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, ofsubject body weight per day, one or more times a day, to obtain thedesired therapeutic and/or prophylactic effect.

It will be appreciated that dose ranges as described herein provideguidance for the administration of provided pharmaceutical compositionsto an adult. The amount to be administered to, for example, a child oran adolescent can be determined by a medical practitioner or personskilled in the art and can be lower or the same as that administered toan adult.

It will be also appreciated that a compound or composition, as describedherein, can be administered in combination with one or more additionalpharmaceutical agents (e.g., therapeutically and/or prophylacticallyactive agents). The compounds or compositions can be administered incombination with additional pharmaceutical agents that improve theiractivity (e.g., activity (e.g., potency and/or efficacy) in treating adisease in a subject in need thereof, in preventing a disease in asubject in need thereof, in reducing the risk of developing a disease ina subject in need thereof, in inhibiting the replication of a virus, inkilling a virus, in inhibiting the activity of a bromodomain-containingprotein in a subject or cell, in inhibiting the activity of abromodomain in a subject or cell, in inhibiting the binding of abromodomain of a bromodomain-containing protein to an acetyl-lysineresidue of a second protein (e.g., a histone) in a subject or cell, inmodulating (e.g., inhibiting) the transcription elongation, inmodulating (e.g., inhibiting) the expression (e.g., transcription) of agene that is regulated by a bromodomain-containing protein in a subjector cell, in inducing apoptosis of a cell, in inducing apoptosis in asubject, or in inducing G1 arrest in a subject or cell),bioavailability, and/or safety, reduce drug resistance, reduce and/ormodify their metabolism, inhibit their excretion, and/or modify theirdistribution within the body of a subject. It will also be appreciatedthat the therapy employed may achieve a desired effect for the samedisorder, and/or it may achieve different effects. In certainembodiments, a pharmaceutical composition described herein including acompound described herein and an additional pharmaceutical agent shows asynergistic effect that is absent in a pharmaceutical compositionincluding one of the compound and the additional pharmaceutical agent,but not both.

The compound or composition can be administered concurrently with, priorto, or subsequent to one or more additional pharmaceutical agents, whichmay be useful as, e.g., combination therapies. Pharmaceutical agentsinclude therapeutically active agents. Pharmaceutical agents alsoinclude prophylactically active agents. Pharmaceutical agents includesmall organic molecules such as drug compounds (e.g., compounds approvedfor human or veterinary use by the U.S. Food and Drug Administration asprovided in the Code of Federal Regulations (CFR)), peptides, proteins,carbohydrates, monosaccharides, oligosaccharides, polysaccharides,nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides orproteins, small molecules linked to proteins, glycoproteins, steroids,nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides,antisense oligonucleotides, lipids, hormones, vitamins, and cells. Incertain embodiments, the additional pharmaceutical agent is apharmaceutical agent useful for treating and/or preventing a diseasedescribed herein. Each additional pharmaceutical agent may beadministered at a dose and/or on a time schedule determined for thatpharmaceutical agent. The additional pharmaceutical agents may also beadministered together with each other and/or with the compound orcomposition described herein in a single dose or administered separatelyin different doses. The particular combination to employ in a regimenwill take into account compatibility of the compound described hereinwith the additional pharmaceutical agent(s) and/or the desiredtherapeutic and/or prophylactic effect to be achieved. In general, it isexpected that the additional pharmaceutical agent(s) utilized incombination be utilized at levels that do not exceed the levels at whichthey are utilized individually. In some embodiments, the levels utilizedin combination will be lower than those utilized individually.

The additional pharmaceutical agents include, but are not limited to,anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents,anti-inflammatory agents, immunosuppressants, anti-bacterial agents,anti-viral agents, cardiovascular agents, cholesterol-lowering agents,anti-diabetic agents, anti-allergic agents, contraceptive agents, andpain-relieving agents. In certain embodiments, the additionalpharmaceutical agent is an anti-proliferative agent. In certainembodiments, the additional pharmaceutical agent is an anti-canceragent. In certain embodiments, the additional pharmaceutical agent is ananti-leukemia agent. In certain embodiments, the additionalpharmaceutical agent is ABITREXATE (methotrexate), ADE, Adriamycin RDF(doxorubicin hydrochloride), Ambochlorin (chlorambucil), ARRANON(nelarabine), ARZERRA (ofatumumab), BOSULIF (bosutinib), BUSULFEX(busulfan), CAMPATH (alemtuzumab), CERUBIDINE (daunorubicinhydrochloride), CLAFEN (cyclophosphamide), CLOFAREX (clofarabine),CLOLAR (clofarabine), CVP, CYTOSAR-U (cytarabine), CYTOXAN(cyclophosphamide), ERWINAZE (Asparaginase Erwinia Chrysanthemi),FLUDARA (fludarabine phosphate), FOLEX (methotrexate), FOLEX PFS(methotrexate), GAZYVA (obinutuzumab), GLEEVEC (imatinib mesylate),Hyper-CVAD, ICLUSIG (ponatinib hydrochloride), IMBRUVICA (ibrutinib),LEUKERAN (chlorambucil), LINFOLIZIN (chlorambucil), MARQIBO (vincristinesulfate liposome), METHOTREXATE LPF (methorexate), MEXATE(methotrexate), MEXATE-AQ (methotrexate), mitoxantrone hydrochloride,MUSTARGEN (mechlorethamine hydrochloride), MYLERAN (busulfan), NEOSAR(cyclophosphamide), ONCASPAR (Pegaspargase), PURINETHOL(mercaptopurine), PURIXAN (mercaptopurine), Rubidomycin (daunorubicinhydrochloride), SPRYCEL (dasatinib), SYNRIBO (omacetaxinemepesuccinate), TARABINE PFS (cytarabine), TASIGNA (nilotinib), TREANDA(bendamustine hydrochloride), TRISENOX (arsenic trioxide), VINCASAR PFS(vincristine sulfate), ZYDELIG (idelalisib), or a combination thereof.In certain embodiments, the additional pharmaceutical agent is ananti-lymphoma agent. In certain embodiments, the additionalpharmaceutical agent is ABITREXATE (methotrexate), ABVD, ABVE, ABVE-PC,ADCETRIS (brentuximab vedotin), ADRIAMYCIN PFS (doxorubicinhydrochloride), ADRIAMYCIN RDF (doxorubicin hydrochloride), AMBOCHLORIN(chlorambucil), AMBOCLORIN (chlorambucil), ARRANON (nelarabine),BEACOPP, BECENUM (carmustine), BELEODAQ (belinostat), BEXXAR(tositumomab and iodine I 131 tositumomab), BICNU (carmustine),BLENOXANE (bleomycin), CARMUBRIS (carmustine), CHOP, CLAFEN(cyclophosphamide), COPP, COPP-ABV, CVP, CYTOXAN (cyclophosphamide),DEPOCYT (liposomal cytarabine), DTIC-DOME (dacarbazine), EPOCH, FOLEX(methotrexate), FOLEX PFS (methotrexate), FOLOTYN (pralatrexate),HYPER-CVAD, ICE, IMBRUVICA (ibrutinib), INTRON A (recombinant interferonalfa-2b), ISTODAX (romidepsin), LEUKERAN (chlorambucil), LINFOLIZIN(chlorambucil), Lomustine, MATULANE (procarbazine hydrochloride),METHOTREXATE LPF (methotrexate), MEXATE (methotrexate), MEXATE-AQ(methotrexate), MOPP, MOZOBIL (plerixafor), MUSTARGEN (mechlorethaminehydrochloride), NEOSAR (cyclophosphamide), OEPA, ONTAK (denileukindiftitox), OPPA, R-CHOP, REVLIMID (lenalidomide), RITUXAN (rituximab),STANFORD V, TREANDA (bendamustine hydrochloride), VAMP, VELBAN(vinblastine sulfate), VELCADE (bortezomib), VELSAR (vinblastinesulfate), VINCASAR PFS (vincristine sulfate), ZEVALIN (ibritumomabtiuxetan), ZOLINZA (vorinostat), ZYDELIG (idelalisib), or a combinationthereof. In certain embodiments, the additional pharmaceutical agent isREVLIMID (lenalidomide), DACOGEN (decitabine), VIDAZA (azacitidine),CYTOSAR-U (cytarabine), IDAMYCIN (idarubicin), CERUBIDINE(daunorubicin), LEUKERAN (chlorambucil), NEOSAR (cyclophosphamide),FLUDARA (fludarabine), LEUSTATIN (cladribine), or a combination thereof.In certain embodiments, the additional pharmaceutical agent isABITREXATE (methotrexate), ABRAXANE (paclitaxel albumin-stabilizednanoparticle formulation), AC, AC-T, ADE, ADRIAMYCIN PFS (doxorubicinhydrochloride), ADRUCIL (fluorouracil), AFINITOR (everolimus), AFINITORDISPERZ (everolimus), ALDARA (imiquimod), ALIMTA (pemetrexed disodium),AREDIA (pamidronate disodium), ARIMIDEX (anastrozole), AROMASIN(exemestane), AVASTIN (bevacizumab), BECENUM (carmustine), BEP, BICNU(carmustine), BLENOXANE (bleomycin), CAF, CAMPTOSAR (irinotecanhydrochloride), CAPOX, CAPRELSA (vandetanib), CARBOPLATIN-TAXOL,CARMUBRIS (carmustine), CASODEX (bicalutamide), CEENU (lomustine),CERUBIDINE (daunorubicin hydrochloride), CERVARIX (recombinant HPVbivalent vaccine), CLAFEN (cyclophosphamide), CMF, COMETRIQ(cabozantinib-s-malate), COSMEGEN (dactinomycin), CYFOS (ifosfamide),CYRAMZA (ramucirumab), CYTOSAR-U (cytarabine), CYTOXAN(cyclophosphamide), DACOGEN (decitabine), DEGARELIX, DOXIL (doxorubicinhydrochloride liposome), DOXORUBICIN HYDROCHLORIDE, DOX-SL (doxorubicinhydrochloride liposome), DTIC-DOME (dacarbazine), EFUDEX (fluorouracil),ELLENCE (epirubicin hydrochloride), ELOXATIN (oxaliplatin), ERBITUX(cetuximab), ERIVEDGE (vismodegib), ETOPOPHOS (etoposide phosphate),EVACET (doxorubicin hydrochloride liposome), FARESTON (toremifene),FASLODEX (fulvestrant), FEC, FEMARA (letrozole), FLUOROPLEX(fluorouracil), FOLEX (methotrexate), FOLEX PFS (methotrexate), FOLFIRI,FOLFIRI-BEVACIZUMAB, FOLFIRI-CETUXIMAB, FOLFIRINOX, FOLFOX, FU-LV,GARDASIL (recombinant human papillomavirus (HPV) quadrivalent vaccine),GEMCITABINE-CISPLATIN, GEMCITABINE-OXALIPLATIN, GEMZAR (gemcitabinehydrochloride), GILOTRIF (afatinib dimaleate), GLEEVEC (imatinibmesylate), GLIADEL (carmustine implant), GLIADEL WAFER (carmustineimplant), HERCEPTIN (trastuzumab), HYCAMTIN (topotecan hydrochloride),IFEX (ifosfamide), IFOSFAMIDUM (ifosfamide), INLYTA (axitinib), INTRON A(recombinant interferon alfa-2b), IRESSA (gefitinib), IXEMPRA(ixabepilone), JAKAFI (ruxolitinib phosphate), JEVTANA (cabazitaxel),KADCYLA (ado-trastuzumab emtansine), KEYTRUDA (pembrolizumab), KYPROLIS(carfilzomib), LIPODOX (doxorubicin hydrochloride liposome), LUPRON(leuprolide acetate), LUPRON DEPOT (leuprolide acetate), LUPRON DEPOT-3MONTH (leuprolide acetate), LUPRON DEPOT-4 MONTH (leuprolide acetate),LUPRON DEPOT-PED (leuprolide acetate), MEGACE (megestrol acetate),MEKINIST (trametinib), METHAZOLASTONE (temozolomide), METHOTREXATE LPF(methotrexate), MEXATE (methotrexate), MEXATE-AQ (methotrexate),MITOXANTRONE HYDROCHLORIDE, MITOZYTREX (mitomycin c), MOZOBIL(plerixafor), MUSTARGEN (mechlorethamine hydrochloride), MUTAMYCIN(mitomycin c), MYLOSAR (azacitidine), NAVELBINE (vinorelbine tartrate),NEOSAR (cyclophosphamide), NEXAVAR (sorafenib tosylate), NOLVADEX(tamoxifen citrate), NOVALDEX (tamoxifen citrate), OFF, PAD, PARAPLAT(carboplatin), PARAPLATIN (carboplatin), PEG-INTRON (peginterferonalfa-2b), PEMETREXED DISODIUM, PERJETA (pertuzumab), PLATINOL(cisplatin), PLATINOL-AQ (cisplatin), POMALYST (pomalidomide),prednisone, PROLEUKIN (aldesleukin), PROLIA (denosumab), PROVENGE(sipuleucel-t), REVLIMID (lenalidomide), RUBIDOMYCIN (daunorubicinhydrochloride), SPRYCEL (dasatinib), STIVARGA (regorafenib), SUTENT(sunitinib malate), SYLATRON (peginterferon alfa-2b), SYLVANT(siltuximab), SYNOVIR (thalidomide), TAC, TAFINLAR (dabrafenib),TARABINE PFS (cytarabine), TARCEVA (erlotinib hydrochloride), TASIGNA(nilotinib), TAXOL (paclitaxel), TAXOTERE (docetaxel), TEMODAR(temozolomide), THALOMID (thalidomide), TOPOSAR (etoposide), TORISEL(temsirolimus), TPF, TRISENOX (arsenic trioxide), TYKERB (lapatinibditosylate), VECTIBIX (panitumumab), VEIP, VELBAN (vinblastine sulfate),VELCADE (bortezomib), VELSAR (vinblastine sulfate), VEPESID (etoposide),VIADUR (leuprolide acetate), VIDAZA (azacitidine), VINCASAR PFS(vincristine sulfate), VOTRIENT (pazopanib hydrochloride), WELLCOVORIN(leucovorin calcium), XALKORI (crizotinib), XELODA (capecitabine),XELOX, XGEVA (denosumab), XOFIGO (radium 223 dichloride), XTANDI(enzalutamide), YERVOY (ipilimumab), ZALTRAP (ziv-aflibercept), ZELBORAF(vemurafenib), ZOLADEX (goserelin acetate), ZOMETA (zoledronic acid),ZYKADIA (ceritinib), ZYTIGA (abiraterone acetate), or a combinationthereof. In certain embodiments, the additional pharmaceutical agent isan anti-viral agent. In certain embodiments, the additionalpharmaceutical agent is a binder of a bromodomain-containing protein. Incertain embodiments, the additional pharmaceutical agent is a binder ofa bromodomain. In certain embodiments, the additional pharmaceuticalagent is a binder or inhibitor of a bromodomain-containing protein. Incertain embodiments, the additional pharmaceutical agent is an binder orinhibitor of a bromodomain. In certain embodiments, the additionalpharmaceutical agent is selected from the group consisting of epigeneticor transcriptional modulators (e.g., DNA methyltransferase inhibitors,histone deacetylase inhibitors (HDAC inhibitors), lysinemethyltransferase inhibitors), antimitotic drugs (e.g., taxanes andvinca alkaloids), hormone receptor modulators (e.g., estrogen receptormodulators and androgen receptor modulators), cell signaling pathwayinhibitors (e.g., tyrosine kinase inhibitors), modulators of proteinstability (e.g., proteasome inhibitors), Hsp90 inhibitors,glucocorticoids, all-trans retinoic acids, and other agents that promotedifferentiation. In certain embodiments, the compounds described hereinor pharmaceutical compositions can be administered in combination withan anti-cancer therapy including, but not limited to, surgery, radiationtherapy, transplantation (e.g., stem cell transplantation, bone marrowtransplantation), immunotherapy), viral agent. In certain embodiments,the additional pharmaceutical agent is a binder of abromodomain-containing protein. In certain embodiments, the additionalpharmaceutical agent is a binder of a bromodomain. In certainembodiments, the additional pharmaceutical agent is a binder orinhibitor of a bromodomain-containing protein. In certain embodiments,the additional pharmaceutical agent is an binder or inhibitor of abromodomain. In certain embodiments, the additional pharmaceutical agentis selected from the group consisting of epigenetic or transcriptionalmodulators (e.g., DNA methyltransferase inhibitors, histone deacetylaseinhibitors (HDAC inhibitors), lysine methyltransferase inhibitors),antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptormodulators (e.g., estrogen receptor modulators and androgen receptormodulators), cell signaling pathway inhibitors (e.g., tyrosine kinaseinhibitors), modulators of protein stability (e.g., proteasomeinhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoicacids, and other agents that promote differentiation. In certainembodiments, the compounds described herein or pharmaceuticalcompositions can be administered in combination with an anti-cancertherapy including, but not limited to, surgery, radiation therapy, andchemotherapy.

Also encompassed by the disclosure are kits (e.g., pharmaceuticalpacks). The kits provided may comprise a pharmaceutical composition orcompound described herein and a container (e.g., a vial, ampule, bottle,syringe, and/or dispenser package, or other suitable container). In someembodiments, provided kits may optionally further include a secondcontainer comprising a pharmaceutical excipient for dilution orsuspension of a pharmaceutical composition or compound described herein.In some embodiments, the pharmaceutical composition or compounddescribed herein provided in the first container and the secondcontainer are combined to form one unit dosage form.

Thus, in one aspect, provided are kits including a first containercomprising a compound described herein, or a pharmaceutically acceptablesalt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer,isotopically labeled derivative, or prodrug thereof, or a pharmaceuticalcomposition thereof. In certain embodiments, the kits are useful fortreating and/or preventing a disease described herein in a subject inneed thereof. In certain embodiments, the kits are useful for treating adisease described herein in a subject in need thereof. In certainembodiments, the kits are useful for preventing a disease describedherein in a subject in need thereof. In certain embodiments, the kitsare useful for reducing the risk of developing a disease describedherein in a subject in need thereof. In certain embodiments, the kitsare useful for male contraception. In certain embodiments, the kits areuseful for inhibiting sperm formation. In certain embodiments, the kitsare useful for in inhibiting the replication of a virus. In certainembodiments, the kits are useful for killing a virus. In certainembodiments, the kits are useful for inhibiting the activity (e.g.,aberrant activity, such as increased activity) of abromodomain-containing protein in a subject or cell. In certainembodiments, the kits are useful for inhibiting the activity (e.g.,aberrant activity, such as increased activity) of a bromodomain in asubject or cell. In certain embodiments, the kits are useful forinhibiting the binding of a bromodomain of a bromodomain-containingprotein to an acetyl-lysine residue of a second protein (e.g., ahistone) in a subject or cell. In certain embodiments, the kits areuseful for modulating (e.g., inhibiting) the transcriptional elongationin a subject or cell. In certain embodiments, the kits are useful formodulating (e.g., down-regulating or inhibiting) the expression (e.g.,transcription) of a gene that is regulated by a bromodomain-containingprotein in a subject or cell. In certain embodiments, the kits areuseful for inducing apoptosis of a cell. In certain embodiments, thekits are useful for inducing apoptosis in a subject. In certainembodiments, the kits are useful for inducing G1 arrest in a subject orcell.

In certain embodiments, the kits are useful for screening a library ofcompounds to identify a compound that is useful in a method of thedisclosure.

In certain embodiments, a kit described herein further includesinstructions for using the kit, such as instructions for using the kitin a method of the disclosure (e.g., instructions for administering acompound or pharmaceutical composition described herein to a subject). Akit described herein may also include information as required by aregulatory agency such as the U.S. Food and Drug Administration (FDA).In certain embodiments, the information included in the kits isprescribing information. In certain embodiments, the kits andinstructions provide for treating and/or preventing a disease describedherein in a subject in need thereof. In certain embodiments, the kitsand instructions provide for treating a disease described herein in asubject in need thereof. In certain embodiments, the kits andinstructions provide for preventing a disease described herein in asubject in need thereof. In certain embodiments, the kits andinstructions provide for reducing the risk of developing a diseasedescribed herein in a subject in need thereof. In certain embodiments,the kits and instructions provide for male contraception. In certainembodiments, the kits and instructions provide for inhibiting thereplication of a virus. In certain embodiments, the kits andinstructions provide for killing a virus. In certain embodiments, thekits and instructions provide for inhibiting the activity (e.g.,aberrant activity, such as increased activity) of abromodomain-containing protein in a subject or cell. In certainembodiments, the kits and instructions provide for inhibiting theactivity (e.g., aberrant activity, such as increased activity) of abromodomain in a subject or cell. In certain embodiments, the kits andinstructions provide for inhibiting the binding of a bromodomain of abromodomain-containing protein to an acetyl-lysine residue of a secondprotein (e.g., a histone) in a subject or cell. In certain embodiments,the kits and instructions provide for modulating (e.g., inhibiting) thetranscriptional elongation. In certain embodiments, the kits andinstructions provide for modulating (e.g., down-regulating orinhibiting) the expression (e.g., transcription) of a gene that isregulated by a bromodomain-containing protein in a subject or cell. Incertain embodiments, the kits and instructions provide for inducingapoptosis of an in vitro cell. In certain embodiments, the kits andinstructions provide for inducing apoptosis of a cell in a subject. Incertain embodiments, the kits and instructions provide for inducing G1arrest in a subject or cell. In certain embodiments, the kits andinstructions provide for screening a library of compounds to identify acompound that is useful in a method of the disclosure. A kit describedherein may include one or more additional pharmaceutical agentsdescribed herein as a separate composition.

Methods of Treatment and Uses

The present disclosure provides methods for the treatment of a widerange of diseases, such as diseases associated with bromodomains,diseases associated with the activity (e.g., aberrant activity) ofbromodomains, diseases associated with bromodomain-containing proteins,and disease associated with the activity (e.g., aberrant activity ) ofbromodomain-containing proteins. Exemplary diseases include, but are notlimited to, proliferative diseases, cardiovascular diseases, viralinfections, fibrotic diseases, neurological diseases, metabolicdiseases, endocrine diseases, and radiation poisoning. Also provided bythe present disclosure are methods for male contraception. The presentdisclosure also provides methods of inhibiting sperm formation. Thepresent disclosure further provides methods of inhibiting the activity(e.g., aberrant activity, such as increased activity) of a bromodomainor bromodomain-containing protein, methods of inhibiting the binding ofa bromodomain of a bromodomain-containing protein to an acetyl-lysineresidue of a second protein (e.g., a histone), methods of modulating(e.g., inhibiting) the transcriptional elongation, methods of modulating(e.g., down-regulating or inhibiting) the expression (e.g.,transcription) of a gene that is regulated by a bromodomain-containingprotein, methods of inducing apoptosis, and methods of inducing G1arrest.

Gene regulation is fundamentally governed by reversible, non-covalentassembly of macromolecules. Signal transduction to RNA polymeraserequires higher-ordered protein complexes, spatially regulated byassembly factors capable of interpreting the post-translationalmodification states of chromatin. Epigenetic readers are structurallydiverse proteins, and each of the epigenetic readers possesses one ormore evolutionarily conserved effector modules, which recognize covalentmodifications of proteins (e.g., histones) or DNA. The e-N-acetylationof lysine residues (Kac) on histone tails is associated with an openchromatin architecture and transcriptional activation. Context-specificmolecular recognition of acetyl-lysine is principally mediated bybromodomains.

Bromodomain-containing proteins are of substantial biological interest,as components of transcription factor complexes (e.g., TBP (TATA boxbinding protein)-associated factor 1 (TAF1), CREB-binding protein (CBPor CREBBP), P300/CBP-associated factor (PCAF), and Gcn5) anddeterminants of epigenetic memory. There are 41 human proteinscontaining a total of 57 diverse bromodomains. Despite large sequencevariations, all bromodomains share a conserved fold comprising aleft-handed bundle of four alpha helices (α_(Z), α_(A), α_(B), andα_(C)), linked by diverse loop regions (ZA and BC loops) that determinesubstrate specificity. Co-crystal structures with peptidic substratesshowed that the acetyl-lysine is recognized by a central hydrophobiccavity and is anchored by a hydrogen bond with an asparagine residuepresent in most bromodomains. The bromo and extra-terminal (BET) family(e.g., BRD2, BRD3, BRD4 and BRDT) shares a common domain architecturecomprising two N-terminal bromodomains that exhibit a high degree ofsequence conservation, and a more divergent C-terminal recruitmentdomain.

Recent research has established a compelling rationale for targetingBRD4 in cancer. BRD4 functions to facilitate cell cycle progression, andknock-down in cultured cancer cell lines prompts G1 arrest. BRD4 is animportant mediator of transcriptional elongation, functioning to recruitthe positive transcription elongation factor complex (P-TEFb). Cyclindependent kinase-9, a core component of P-TEFb, is a validated target inchronic lymphocytic leukemia, and has recently been linked to c-Mycdependent transcription. Bromodomains present in BRD4 recruit P-TEFb tomitotic chromosomes resulting in increased expression of growthpromoting genes. BRD4 remains bound to transcriptional start sites ofgenes expressed during M/G1 but has not been found present at startsites that are expressed later in the cell cycle. Knockdown of BRD4 inproliferating cells has been shown to lead to G1 arrest and apoptosis bydecreasing expression levels of genes important for mitotic progressionand survival.

Importantly, BRD4 has recently been identified as a component of arecurrent t(15;19) chromosomal translocation in an aggressive form ofhuman squamous cell carcinoma. Such translocations express the tandemN-terminal bromodomains of BRD4 as an in-frame chimera with the nuclearprotein in testis (NUT) protein, genetically defining the NUT midlinecarcinoma (NMC). Functional studies in patient-derived NMC cell lineshave validated the essential role of the BRD4-NUT oncoprotein inmaintaining the characteristic proliferation advantage anddifferentiation block of this malignancy. Notably, RNA silencing ofBRD4-NUT gene expression arrests proliferation and prompts squamousdifferentiation with a marked increase in cytokeratin expression. Abromodomain may also down-regulates Myc and other transcriptionalfactors, such as interleukin 7 receptor (IL7R). These observationsunderscore the utility and therapeutic potential of a binder orinhibitor of bromodomain-containing proteins.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain-containing protein in a subject.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain-containing protein in a biological sample(e.g., a cell).

In certain embodiments, the bromodomain-containing protein is abromodomain-containing protein described herein (e.g., a BET protein,such as BRD2, BRD3, BRD4, or BRDT). In certain embodiments, the activityof a bromodomain-containing protein in a subject or a biological sample(e.g., a cell) is inhibited by the described methods. In certainembodiments, the activity of a bromodomain-containing protein in asubject or a biological sample (e.g., a cell) is inhibited by thedescribed methods by at least about 1%, at least about 3%, at leastabout 10%, at least about 20%, at least about 30%, at least about 40%,at least about 50%, at least about 60%, at least about 70%, at leastabout 80%, at least about 90%, at least about 95%, or at least about98%. In certain embodiments, the activity of a bromodomain-containingprotein in a subject or a biological sample (e.g., a cell) is inhibitedby the described methods by at most about 90%, at most about 80%, atmost about 70%, at most about 60%, at most about 50%, at most about 40%,at most about 30%, at most about 20%, at most about 10%, at most about3%, or at most about 1%. Combinations of the above-referenced ranges(e.g., at least about 10% and at most about 50%) are also within thescope of the disclosure. Other ranges are also possible. In someembodiments, the activity of a bromodomain-containing protein in asubject or a biological sample (e.g., a cell) is selectively inhibitedby the described methods. In some embodiments, the activity of abromodomain-containing protein in a subject or a biological sample(e.g., a cell) is selectively inhibited by the described methods,compared to the activity of a kinase (e.g., a MAP kinase, a mitoticspindle kinase, a polo kinase). In other embodiments, the activity of abromodomain-containing protein in a subject or a biological sample(e.g., a cell) is non-selectively inhibited by the described methods. Incertain embodiments, the cytokine level and/or histamine release arereduced by the described methods.

In certain embodiments, the activity of a bromodomain-containing proteinis an aberrant activity of the bromodomain-containing protein. Incertain embodiments, the activity of a bromodomain-containing protein isan increased activity of the bromodomain-containing protein. In certainembodiments, the activity of a bromodomain-containing protein is reducedby a method of the disclosure.

In certain embodiments, the subject is an animal. The animal may be ofeither sex and may be at any stage of development. In certainembodiments, the subject is a male. In certain embodiments, the subjectis a female. In certain embodiments, the subject described herein is ahuman. In certain embodiments, the subject described herein is a humanmale. In certain embodiments, the subject described herein is a humanfemale. In certain embodiments, the subject is a human diagnosed ashaving a disease described herein. In certain embodiments, the subjectis a human diagnosed as being at a higher-than-normal risk of developinga disease described herein. In certain embodiments, the subject is ahuman suspected of having a disease described herein. In certainembodiments, the subject is a non-human animal. In certain embodiments,the subject is a fish. In certain embodiments, the subject is a mammal.In certain embodiments, the subject is a non-human mammal. In certainembodiments, the subject is a human or non-human mammal. In certainembodiments, the subject is a domesticated animal, such as a dog, cat,cow, pig, horse, sheep, or goat. In certain embodiments, the subject isa companion animal such as a dog or cat. In certain embodiments, thesubject is a livestock animal such as a cow, pig, horse, sheep, or goat.In certain embodiments, the subject is a zoo animal. In anotherembodiment, the subject is a research animal such as a rodent (e.g.,mouse, rat), dog, pig, or non-human primate. In certain embodiments, theanimal is a genetically engineered animal. In certain embodiments, theanimal is a transgenic animal (e.g., transgenic mice and transgenicpigs).

In certain embodiments, a cell described herein is in vitro. In certainembodiments, a cell is ex vivo. In certain embodiments, a cell is invivo.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain in a subject.

In another aspect, the present disclosure provides methods of inhibitingthe activity of a bromodomain in a biological sample (e.g., a cell).

In certain embodiments, the activity of a bromodomain is an aberrantactivity of the bromodomain. In certain embodiments, the activity of abromodomain is an increased activity of the bromodomain. In certainembodiments, the activity of a bromodomain is reduced by a method of thedisclosure.

Another aspect of the present disclosure relates to methods ofinhibiting the binding of a bromodomain of a bromodomain-containingprotein to an acetyl-lysine residue of a second protein (e.g., ahistone) in a subject.

Another aspect of the present disclosure relates to methods ofinhibiting the binding of a bromodomain of a bromodomain-containingprotein to an acetyl-lysine residue of a second protein (e.g., ahistone) in a biological sample (e.g., a cell).

In certain embodiments, the second protein is a protein with anacetyl-lysine residue. In certain embodiments, the second protein is nota bromodomain-containing protein. In certain embodiments, the secondprotein is a histone. In certain embodiments, the histone is selectedfrom the group consisting of H1, H2A, H2B, H3, H4, and H5. In certainembodiments, the binding of a bromodomain of the bromodomain-containingprotein to an acetyl-lysine residue of the second protein (e.g., ahistone) is inhibited by the described methods.

In another aspect, the present disclosure provides methods of modulating(e.g., inhibiting) the transcription elongation. In certain embodiments,the transcription elongation is modulated (e.g., inhibited) by thedescribed methods.

In another aspect, the present disclosure provides methods of modulatingthe expression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein in a subject.

In another aspect, the present disclosure provides methods of modulatingthe expression (e.g., transcription) of a gene that is regulated by abromodomain-containing protein in a biological sample (e.g., a cell).

In certain embodiments, the present disclosure provides methods ofdown-regulating or inhibiting the expression (e.g., transcription) of agene that is regulated by a bromodomain-containing protein in a subjector biological sample (e.g., a cell). Without wishing to be bound by anyparticular theory, the compounds and pharmaceutical compositionsdescribed herein may be able to interfere with the binding of abromodomain-containing protein to a transcriptional start site of thegene. In certain embodiments, the compounds and pharmaceuticalcompositions described herein interfere with the recognition ofacetyl-lysine by a bromodomain or bromodomain-containing protein duringthe expression (e.g., transcription) of the gene. In certainembodiments, the compounds and pharmaceutical compositions describedherein interfere with the anchoring of a bromodomain-containing proteinto an acetylated chromatin (e.g., a bromodomain of thebromodomain-containing protein being anchored to an acetyl-lysine of theacetylated chromatin) during the expression (e.g., transcription) of thegene. In certain embodiments, the expression (e.g., transcription) of agene that is regulated by a bromodomain-containing protein in a subjector biological sample (e.g., a cell) is modulated by the describedmethods. In certain embodiments, the expression (e.g., transcription) ofa gene that is regulated by a bromodomain-containing protein in asubject or biological sample (e.g., a cell) is down-regulated orinhibited by the described methods. In certain embodiments, the genethat is regulated by a bromodomain-containing protein is an oncogene.

Another aspect of the present disclosure relates to methods of treatinga disease in a subject in need thereof.

associated with a bromodomain-containing protein. In certainembodiments, the disease is associated with the activity of abromodomain-containing protein. In certain embodiments, the disease isassociated with the aberrant activity or increased activity of abromodomain-containing protein.

In certain embodiments, the disease is associated with a bromodomain(e.g., a bromodomain of a bromodomain-containing protein). In certainembodiments, the disease is associated with the activity of abromodomain. In certain embodiments, the disease is associated with theaberrant activity or increased activity of a bromodomain. In certainembodiments, the disease is associated with the function (e.g.,dysfunction) of a bromodomain.

In certain embodiments, the disease described herein is driven by atranscriptional activator. In certain embodiments, the transcriptionalactivator is Myc. In certain embodiments, the disease is associated witha NUT rearrangement. In certain embodiments, the disease is associatedwith aberrant Myc function. In certain embodiments, the disease isassociated with the interleukin 7 receptor (IL7R).

In certain embodiments, the disease is a proliferative disease (e.g., aproliferative disease described herein). In certain embodiments, thedisease is cancer (e.g., a cancer described herein). In certainembodiments, the disease is lung cancer. In certain embodiments, thedisease is multiple myeloma. In certain embodiments, the disease isneuroblastoma. In certain embodiments, the disease is colon cancer. Incertain embodiments, the disease is testicular cancer. In certainembodiments, the disease is ovarian cancer. In certain embodiments, thedisease is lung cancer (e.g., small-cell lung cancer or non-small-celllung cancer). In certain embodiments, the disease is NUT midlinecarcinoma (e.g., BRD3 NUT midline carcinoma or BRD4 NUT midlinecarcinoma). In certain embodiments, the disease is leukemia. In certainembodiments, the disease is mixed-lineage leukemia (MLL). In certainembodiments, the disease is acute myelocytic leukemia (AML),biphenotypic B myelomonocytic leukemia, or erythroleukemia. In certainembodiments, the disease is selected from the group consisting ofBurkitt's lymphoma, breast cancer, colon cancer, neuroblastoma, glialblastoma multiforme, chronic lymphocytic leukemia, and squamous cellcarcinoma.

In certain embodiments, the disease is a benign neoplasm (e.g., a benignneoplasm described herein).

In certain embodiments, the disease is an inflammatory disease (e.g., aninflammatory disease described herein). In certain embodiments, thedisease is a disease that involves an inflammatory response to aninfection with a bacterium, virus, fungus, parasite, and/or protozoon.In certain embodiments, the disease is selected from the groupconsisting of osteoarthritis, acute gout, multiple sclerosis, aninflammatory bowel disease (e.g., Crohn's disease and ulcerativecolitis), neuroinflammation, asthma, a chronic obstructive airwaysdisease, pneumonitis, myositis, eczema, dermatitis, acne, cellulitis, anocclusive disease, thrombosis, alopecia, nephritis, vasculitis,retinitis, uveitis, scleritis, sclerosing cholangitis, hypophysitis,thyroiditis, septic shock, systemic inflammatory response syndrome(SIRS), toxic shock syndrome, acute lung injury, ARDS (adult respiratorydistress syndrome), acute renal failure, burns, pancreatitis (e.g.,acute pancreatitis), post-surgical syndromes, sarcoidosis, Herxheimerreactions, encephalitis, myelitis, meningitis, and malaria. In certainembodiments, the disease is acute or chronic pancreatitis. In certainembodiments, the disease is burns. In certain embodiments, the diseaseis an inflammatory bowel disease. In certain embodiments, the disease isneuroinflammation. In certain embodiments, the disease is sepsis orsepsis syndrome. In certain embodiments, the disease isgraft-versus-host disease (GVHD).

In certain embodiments, the disease is an autoimmune disease (e.g., anautoimmune disease described herein). In certain embodiments, thedisease is rheumatoid arthritis. In certain embodiments, the disease ispsoriasis, systemic lupus erythematosus, vitiligo, a bullous skindisease.

In certain embodiments, the disease is a cardiovascular disease. Incertain embodiments, the disease is atherogenesis or atherosclerosis. Incertain embodiments, the disease is arterial stent occlusion, heartfailure (e.g., congestive heart failure), a coronary arterial disease,myocarditis, pericarditis, a cardiac valvular disease, stenosis,restenosis, in-stent-stenosis, angina pectoris, myocardial infarction,acute coronary syndromes, coronary artery bypass grafting, acardio-pulmonary bypass procedure, endotoxemia, ischemia-reperfusioninjury, cerebrovascular ischemia (stroke), renal reperfusion injury,embolism (e.g., pulmonary, renal, hepatic, gastro-intestinal, orperipheral limb embolism), or myocardial ischemia.

In certain embodiments, the disease is a viral infection. In certainembodiments, the disease is an infection caused by DNA virus. In certainembodiments, the disease is an infection caused by a dsDNA virus. Incertain embodiments, the disease is an infection caused by an ssDNAvirus. In certain embodiments, the disease is an infection caused by anRNA virus. In certain embodiments, the disease is an infection caused bya dsRNA virus. In certain embodiments, the disease is an infectioncaused by a (+)ssRNA virus. In certain embodiments, the disease is aninfection caused by a (−)ssRNA virus. In certain embodiments, thedisease is an infection caused by a reverse transcribing (RT) virus. Incertain embodiments, the disease is an infection caused by an ssRNA-RTvirus. In certain embodiments, the disease is an infection caused by adsDNA-RT virus. In certain embodiments, the disease is an infectioncaused by human immunodeficiency virus (HIV). In certain embodiments,the disease is an infection caused by acquired immunodeficiency syndrome(AIDS). In certain embodiments, the disease is an infection caused byhuman papillomavirus (HPV). In certain embodiments, the disease is aninfection caused by hepatitis C virus (HCV). In certain embodiments, thedisease is an infection caused by a herpes virus (e.g., herpes simplexvirus (HSV)). In certain embodiments, the disease is an infection causedby Ebola virus. In certain embodiments, the disease is an infectioncaused by severe acute respiratory syndrome (SARS). In certainembodiments, the disease is an infection caused by influenza virus. Incertain embodiments, the disease is an infection caused by an influenzavirus. In certain embodiments, the disease is an infection caused by aninfluenza A virus. In certain embodiments, the disease is human flu(e.g., human flu caused by H1N1, H2N2, H3N2, H5N1, H7N7, H1N2, H9N2,H7N2, H7N3, or H10N7 virus). In certain embodiments, the disease is birdflu (e.g., bird flu caused by H5N1 or H7N9 virus). In certainembodiments, the disease is swine influenza (e.g., swine influenzacaused by H1N1, H1N2, H2N1, H3N1, H3N2, H2N3, or influenza C virus). Incertain embodiments, the disease is equine influenza (e.g., equineinfluenza caused by H7N7 or H3N8 virus). In certain embodiments, thedisease is canine influenza (e.g., canine influenza caused by H3N8virus). In certain embodiments, the disease is an infection caused by aninfluenza B virus. In certain embodiments, the disease is an infectioncaused by an influenza C virus. In certain embodiments, the disease isDengue fever, Dengue hemorrhagic fever (DHF), Dengue shock syndrome(DSS), hepatitis A, hepatitis B, hepatitis D, hepatitis E, hepatitis F,infection caused by Coxsackie A virus, infection caused by Coxsackie Bvirus, fulminant viral hepatitis, viral myocarditis, infection caused byparainfluenza virus, infection caused by an RS virus (RSV) (e.g., RSVbronchiolitis, RSV pneumonia, especially an infant and childhoodinfection caused by RSV and RSV pneumonia in the patients withcardiopulmonary disorders), infection caused by measles virus, infectioncaused by vesicular stomatitis virus, infection caused by rabies virus,Japanese encephalitis, infection caused by Junin virus, infection causedby human cytomegalovirus, infection caused by varicellovirus, infectioncaused by cytomegalovirus, infection caused by muromegalovirus,infection caused by proboscivirus, infection caused by roseolovirus,infection caused by lymphocryptovirus, infection caused by macavirus,infection caused by percavirus, infection caused by rhadinovirus,infection caused by poliovirus, infection caused by Marburg virus,infection caused by Lassa fever virus, Venezuelan equine encephalitis,infection caused by Rift Valley Fever virus, infection caused by Koreanhemorrhagic fever virus, infection caused by Crimean-Congo hemorrhagicfever virus, encephalitis, Saint Louise encephalitis, Kyasanur Forestdisease, Murray Valley encephalitis, tick-borne encephalitis, West Nileencephalitis, yellow fever, infection caused by adenovirus, infectioncaused by poxvirus, or a viral infection in subjects with immunedisorders.

In certain embodiments, the disease is a fibrotic condition. In certainembodiments, the disease is selected from the group consisting of renalfibrosis, post-operative stricture, keloid formation, hepatic cirrhosis,biliary cirrhosis, and cardiac fibrosis. In certain embodiments, thedisease is scleroderma. In certain embodiments, the disease isidiopathic pulmonary fibrosis.

In certain embodiments, the disease is an endocrine disease. In certainembodiments, the disease is Addison's disease.

In certain embodiments, the disease is a neurological disease (e.g.,Alzheimer's disease).

In certain embodiments, the disease is a metabolic disease. In certainembodiments, the disease is diabetes. In certain embodiments, thedisease is type 1 diabetes. In certain embodiments, the disease is TypeII diabetes or gestational diabetes. In certain embodiments, the diseaseis obesity. In certain embodiments, the disease is fatty liver (NASH orotherwise), cachexia, hypercholesterolemia, or a disorder of lipidmetabolism via the regulation of apolipoprotein A1 (APOA1).

In certain embodiments, the disease is radiation poisoning. In certainembodiments, the disease is radiation injury.

In certain embodiments, the disease is acute rejection of transplantedorgans or multi-organ dysfunction syndrome.

In still another aspect, the present disclosure provides methods ofpreventing a disease described herein in a subject in need thereof.

disclosure provides methods of reducing the risk of developing a diseasedescribed herein in a subject in need thereof.

disclosure provides methods for male contraception in a male subject inneed thereof.

In yet another aspect, the present disclosure provides methods ofinhibiting sperm formation in a subject in need thereof.

Another aspect of the present disclosure relates to methods ofinhibiting the replication of a virus. In certain embodiments, thereplication of the virus is inhibited by the described methods.

in vitro. In certain embodiments, the virus is In certain embodiments,the virus described herein is present ex vivo. In certain embodiments,the virus is in vivo.

Another aspect of the present disclosure relates to methods of killing avirus. In certain embodiments, the virus is killed by the describedmethods.

Another aspect of the disclosure relates to methods of inhibiting theinteraction between a bromodomain-containing protein and animmunoglobulin (Ig) regulatory element in a subject.

Another aspect of the disclosure relates to methods of inhibiting theinteraction between a bromodomain-containing protein and animmunoglobulin (Ig) regulatory element in a biological sample (e.g., acell).

Another aspect of the disclosure relates to methods of inducingapoptosis (e.g., apoptosis of a cancer cell) in a cell of a subject.

Another aspect of the disclosure relates to methods of inducingapoptosis in a cell of a biological sample (e.g., an in vitro cell, acancer cell).

Another aspect of the disclosure relates to methods of method forinducing G1 arrest in a cell of a subject.

Another aspect of the disclosure relates to methods of method forinducing G1 arrest in a cell of a biological sample.

In certain embodiments, the methods of the disclosure includeadministering to a subject in need thereof an effective amount of acompound or pharmaceutical composition described herein. In certainembodiments, the methods of the disclosure include administering to asubject in need thereof a therapeutically effective amount of a compoundor pharmaceutical composition described herein. In certain embodiments,the methods of the disclosure include administering to a subject in needthereof a prophylactically effective amount of a compound orpharmaceutical composition described herein. In certain embodiments, themethods of the disclosure include contacting a biological sample (e.g.,a cell) with an effective amount of a compound or pharmaceuticalcomposition described herein. In certain embodiments, the methods of thedisclosure include contacting a virus with an effective amount of acompound or pharmaceutical composition described herein.

In another aspect, the present disclosure provides the compoundsdescribed herein for use in a method of the disclosure, or use in themanufacture of a medicament for use in a method or treatment describedherein.

In still another aspect, the present disclosure provides thepharmaceutical compositions described herein for use in a method of thedisclosure, or use in the manufacture of a medicament for use in amethod or treatment described herein.

Methods of Screening a Library of Compounds

Another aspect of the disclosure relates to methods of screening alibrary of compounds, and pharmaceutical acceptable salts thereof, toidentify a compound, or a pharmaceutical acceptable salt thereof, thatis useful in the methods of the disclosure. In certain embodiments, themethods of screening a library include obtaining at least two differentcompounds described herein; and performing at least one assay using thedifferent compounds described herein. In certain embodiments, at leastone assay is useful in identifying a compound that is useful in thedescribed methods.

Typically, the methods of screening a library of compounds involve atleast one assay. In certain embodiments, the assay is performed todetect one or more characteristics associated with the treatment and/orprevention of a disease described herein, with the inhibition of theactivity of a bromodomain-containing protein, with the inhibition of theactivity of a bromodomain, with the inhibition of the binding of abromodomain to an acetyl-lysine residue of a second protein (e.g., ahistone), with the modulation (e.g., inhibition) of the transcriptionalelongation, with the modulation (e.g., inhibition) of the expression(e.g., transcription) of a gene that is regulated by abromodomain-containing protein, with the induction of apoptosis, and/orwith the induction of G1 arrest. The characteristics may be desiredcharacteristics (e.g., a disease having been treated, a disease havingbeen prevented, the risk of developing a disease having been reduced,the replication of a virus having been inhibited, a virus having beenkilled, the activity of a bromodomain-containing protein having beeninhibited, the activity of a bromodomain, the binding of a bromodomainto an acetyl-lysine residue of a second protein (e.g., a histone) havingbeen inhibited, the transcriptional elongation having been modulated(e.g., having been inhibited), the expression (e.g., transcription) of agene that is regulated by a bromodomain-containing protein having beenmodulated (e.g., having been inhibited), the apoptosis having beeninduced, or the G1 arrest having been induced). The characteristics maybe undesired characteristics (e.g., a disease having not been treated, adisease having not been prevented, the risk of developing a diseasehaving not been reduced, the replication of a virus having not beeninhibited, a virus not having been killed, the activity of abromodomain-containing protein having not been inhibited, the activityof a bromodomain having not been inhibited, the binding of a bromodomainto an acetyl-lysine residue of a second protein (e.g., a histone) havingnot been inhibited, the transcriptional elongation having not beenmodulated (e.g., having not been inhibited), the expression (e.g.,transcription) of a gene that is regulated by a bromodomain-containingprotein having not been modulated (e.g., having not been inhibited), theapoptosis having not been induced, or the G1 arrest having not beeninduced). The assay may be an immunoassay, such as a sandwich-typeassay, competitive binding assay, one-step direct test, two-step test,or blot assay. The step of performing at least one assay may beperformed robotically or manually. In certain embodiments, the assaycomprises (a) contacting a library of compounds with abromodomain-containing protein; and (b) detecting the binding of thelibrary of compounds to the bromodomain-containing protein. In certainembodiments, the assay comprises detecting the specific binding of thelibrary of compounds to the bromodomain-containing protein. In certainembodiments, the assay comprises detecting the specific binding of thelibrary of compounds to a bromodomain of the bromodomain-containingprotein. In certain embodiments, the detected binding of the library ofcompounds to the bromodomain-containing protein is useful in identifyingthe compound that is useful in the methods of the disclosure. In certainembodiments, the step of detecting the binding comprises usingdifferential scanning fluorimetry (DSF), isothermal titrationcalorimetry (ITC), and/or an amplified luminescence proximityhomogeneous assay (ALPHA). The step of performing at least one assay maybe performed in a cell (e.g., a cancer cell) in vitro, ex vivo, or invivo. In certain embodiments, the step of performing at least one assayis performed in a cell (e.g., a cancer cell) in vitro. In certainembodiments, the assay comprises (a) contacting a library of compoundswith a cell; and (b) detecting a decrease in cell proliferation, anincrease in cell death, and/or an increase in cell differentiation. Incertain embodiments, the cell death is apoptotic cell death. In certainembodiments, the cell differentiation is identified by detecting anincrease in cytokeratin expression. In certain embodiments, the step ofperforming at least one assay further comprises detecting a reduction intranscriptional elongation.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The examples describedin this application are offered to illustrate the compounds,pharmaceutical compositions, and methods provided herein and are not tobe construed in any way as limiting their scope.

The IC₅₀ values of the compounds were determined by ALPHASCREENINGassays for BRD4 and BRDT protein. NMC797 cell line is a BRD4 dependantNUT midline carcinoma line. NMC797 showed high denpendency on BRD4inhibition, and the IC₅₀ was determined by ATPLITE assay.

Acetyl-Histone Binding Assay. Assays were performed as describedpreviously with minor modifications from the manufacturer's protocol(PerkinElmer, USA). All reagents were diluted in 50 mM HEPES, 100 mMNaCl, 0.1% BSA, pH 7.4 supplemented with 0.05% CHAPS and allowed toequilibrate to room temperature prior to addition to plates. A 24-point1:2 serial dilution of the ligands was prepared over the range of 150-0μM and 4 μl transferred to low-volume 384-well plates (PROXIPLATE™-384Plus, PerkinElmer, USA), followed by 4 μl of HIS-tagged protein (BRD4/1,250 nM, BRD4/2 and CREBBP, 2000 nM). Plates were sealed and incubated atroom temperature for 30 minutes, before the addition of 4 μl ofbiotinylated peptide at equimolar concentration to the protein [peptidefor BRD4(1) & BRD4(2), and BRDT: H4K5acK8acK12acK16ac,H-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRK(Biotin)-OH; peptide for CREBBP:H3K36ac, Biotin-KSAPATGGVK(Ac)KPHRYRPGT-OH (Cambridge ResearchBiochemicals, UK)]. Plates were sealed and incubated for a further 30minutes, before the addition of 4 μl of streptavidin-coated donor beads(25 μg/ml) and μ4 1 nickel chelate acceptor beads (25 μg/ml) under lowlight conditions. Plates were foil-sealed to protect from light,incubated at room temperature for 60 minutes and read on a PHERASTAR FSplate reader (BMG Labtech, Germany) using an ALPHASCREEN 680excitation/570 emission filter set. IC₅₀ values were calculated in Prism5 (GRAPHPAD Software, USA) after normalization against correspondingDMSO controls and are given as the final concentration of compound inthe 20 μl reaction volume.

Cell Proliferation Assay. Cells were seeded into white, 384-wellmicrotiter plates (Nunc) at 500 cells per well in a total volume of 50μL media. The 797, TT, and TE10 cells were grown in DMEM containing 1%penicillin/streptomycin and 10% FBS. The Per403 cells were grown in DMEMcontaining 1% penicillin/streptomycin and 20% FBS. Compounds weredelivered to microtiter assay plates by robotic pin transfer(PerkinElmer JANUS equipped with a V&P Scientific 100 nL pin tool).Following a 48-hour incubation at 37° C., cells were lysed and wellswere assessed for total ATP content using a commercial proliferationassay (Cell TITERGLO; Promega). Replicate measurements were analyzedwith respect to dose and estimates of IC₅₀ were calculated by logisticregression (GRAPHPAD PRISM).

TABLE E1 IC₅₀ of exemplary compounds for BRDT(1), BRD4(1), and NMC797.IC₅₀ BRDT(1) IC₅₀ BRD4(1) IC₅₀ NMC797 Compound (nM) (nM) (nM) JQ1 77 2921 501 82 36 30 502 61 28 29 503 89 44 42 504 69 27 54 505 75 29 93 601— — — 602 — — — 603 — — — 604 — — — 605 — — —

Pharmacokinetic parameters were determined by administration of acandidate bromodomain inhibitor to male CD1 mice. Intravenous doses weredelivered at 5 mg/kg, and oral doses at 10 mg/kg (N=3). The results arelisted in Table E2 and Table E3 for certain compounds described hereinand for the known inhibitor JQ1. The compound half-life in mice asrevealed by pharmacokinetic analyses of mean whole blood concentrationwith time after iIV injection at 5 mg/kg in male CD1 mice (n=3) for IVinjection, and 10 mg/kg oral. The compound concentration in mouse bloodwas monitored over 24-hour time period to check the compoundconcentration in blood at 5 min, 30 min, 1 hour, 2 hours, 6 hours, 12hours, and 24 hour via a series bleeding.

TABLE E2 Average pharmacokinetic parameters for exemplary compounds (IVadministration). Terminal CL V_(SS) t_(1/2) AUC_(last) AUC_(INF)MRT_(INF) Compound (L/hr/kg) (L/kg) (hr) (hr · ng/mL) (hr · ng/mL) (hr)JQ1 2.35 2.02 0.897 2130 2130 0.861 501  2.20 1.54 1.51 2377 2394 0.718502  1.77 1.48 1.06 2942 2961 0.882 601^(a) — — 11.7 — — — 602^(a) — —21 — — — 603^(a) — — 1 — — — 604^(a) — — 2 — — — 605^(a) — — 0.5 — — —^(a)Compounds 601-605 were administered at 1 mg/kg.

TABLE E3 Average pharmacokinetic parameters of exemplary compounds (oraladministration). Terminal T_(max) C_(max) t_(1/2) AUC_(last) AUC_(INF) FCompound (hr) (ng/mL) (hr) (hr · ng/mL) (hr · ng/mL) (%) JQ1 0.250 11801.39 2040 2090 49.1 501  0.417 1260 1.54 2518 2571 53.7 502  0.500 14271.37 3098 3162 53.4 601^(a) — — — — — 4 602^(a) — — — — — 2 603^(a) — —— — — 20 604^(a) — — — — — 7 605^(a) — — — — — 6 ^(a)Compounds 601-605were administered at 5 mg/kg.

Characterization of Compounds

TABLE F1 Characterization of Compounds Compound NMR and LC-MSCharacterization 601 ¹H NMR (400 MHz, CD₃OD, 25° C.) δ 7.41 (d, J = 8.4Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 6.64 (d, J= 8.8 Hz, 2H), 4.63 (dd, J = 8.4, 5.6 Hz, 1H), 3.57 (dd, J = 15.2, 8.8Hz 1H), 3.35 (dd, J = 15.2, 8.8 Hz 1H), 3.25 (m, 2H), 2.68 (s, 3H),2.47(m, 4H), 2.25 (s, 3H), 1.94 (2H, m), 1.6 (2H, m), 1.5 (1H, m), 1.2 (2H,m). LC-MS for C₂₉H₃₈ClN₇O₂S [M + H]⁺: 568.2 m/z. 602 ¹H NMR (400 MHz,CD3OD, 25° C.) δ 7.49 (t, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H),7.33 (d, J = 8.4 Hz, 2H), 4.65 (dd, J = 8.4, 5.6 Hz, 1H), 3.52 (dd, J =8.4, 5.2 Hz, 2H), 3.40-3.25 (m, 3H), 3.20- 3.01 (m, 2H), 2.68 (s, 3H),2.33 (s, 4H), 2.46-2.34 (m, 5H), 2.00-1.4 (m, 16H). LC-MS forC₃₂H₄₂ClN₇OS [M + H]⁺: 608.3 m/z.

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, wherein: Y is of formula:

wherein: R⁴ is hydrogen, optionally substituted alkyl, optionallysubstituted acyl, or a nitrogen protecting group; L⁴ is unsubstitutedbranched alkylene or substituted alkylene; X⁴ is halogen, —OR^(f),—SR^(f), or —N(R^(f))₂; E is O, S, NR^(E), or CHR^(E), wherein R^(E) isoptionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, or optionally substituted heteroaryl; eachoccurrence of R^(D) is independently hydrogen, halogen, optionallysubstituted alkyl, optionally substituted heteroalkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl, —OR^(f), —SR^(f), —N(R^(f))₂, —NO₂, or —CN, or twoR^(D) attached to adjacent atoms are joined to form an optionallysubstituted carbocyclyl, optionally substituted heterocyclyl, optionallysubstituted aryl, optionally substituted heteroaryl ring; z is 0, 1, or2; and d is 0, 1, 2, 3, or 4; R^(A1) is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, —OR^(f), —SR^(f),—N(R^(f))₂, —NO₂, or —CN; R^(A2) is hydrogen, halogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, —OR^(f), —SR^(f),—N(R^(f))₂, —NO₂, or —CN; X¹ is N or CR⁵, wherein R⁵ is hydrogen,halogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted acyl, —OR^(f),—SR^(f), —N(R^(f))₂, —NO₂, or —CN; R^(B) is hydrogen, halogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, —OR^(f), —SR^(f),—N(R^(f))₂, —NO₂, or —CN; Ring C is aryl or heteroaryl; each occurrenceof R^(C) is independently halogen, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted carbocyclyl, optionally substituted heterocyclyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted acyl, optionally substituted sulfonyl, —OR^(f),—SR^(f), —N(R^(f))₂, —NO₂, or —CN; c is 0, 1, 2, 3, or 4; n is 0, 1, 2,3, or 4; R² is hydrogen, halogen, or optionally substituted alkyl; andeach occurrence of R^(f) is independently hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted carbocyclyl, optionallysubstituted heterocyclyl, optionally substituted aryl, optionallysubstituted heteroaryl, optionally substituted acyl, optionallysubstituted sulfonyl, a sulfur protecting group, an oxygen protectinggroup, or a nitrogen protecting group, or two R^(f) are joined to forman optionally substituted heterocyclic or optionally substitutedheteroaryl ring.
 2. The compound of claim 1, wherein the compound is ofFormula (I-A-1), (I-A-2), (I-B-1), (I-D-1), or (I-D-3):

or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof. 3-11. (canceled)
 12. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Y is of formula:


13. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein L⁴ is unsubstituted branched C₁₋₆ alkylene. 14.(canceled)
 15. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein X⁴ is —OH. 16-20. (canceled)
 21. The compound ofclaim 1, or a pharmaceutically acceptable salt thereof, wherein Y is offormula:


22. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Y is of formula:


23. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Y is of formula:

24-26. (canceled)
 27. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein Y is of formula:


28. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein both R^(A1) and R^(A2) are hydrogen or optionallysubstituted C₁₋₆ alkyl. 29-30. (canceled)
 31. The compound of claim 1,or a pharmaceutically acceptable salt thereof, wherein Ring C is offormula:


32. (canceled)
 33. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein X is N. 34-37. (canceled)
 38. Thecompound of claim 1, wherein the compound is of formula:

or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof.
 39. A pharmaceutical composition comprising a compound of claim1, or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof, and a pharmaceutically acceptable excipient.
 40. (canceled) 41.A method of treating a disease associated with a bromodomain-containingprotein or a bromodomain in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable salt,stereoisomer, or tautomer thereof. 42-45. (canceled)
 46. A method formale contraception, the method comprising administering to a malesubject in need thereof an effective amount of a compound of claim 1, ora pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.47. A method of inhibiting the activity of a bromodomain-containingprotein or a bromodomain in a subject, the method comprisingadministering to the subject an effective amount of a compound of claim1, or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof. 48-53. (canceled)
 54. A method of inhibiting the expression ofa gene that is regulated by a bromodomain-containing protein in asubject, the method comprising administering to the subject an effectiveamount of a compound of claim 1, or a pharmaceutically acceptable salt,stereoisomer, or tautomer thereof.
 55. (canceled)
 56. A method ofinducing apoptosis in a cell in a subject, the method comprisingadministering to the subject an effective amount of a compound of claim1, or a pharmaceutically acceptable salt, stereoisomer, or tautomerthereof.
 57. (canceled)
 58. A method of inducing G1 arrest in a cell ina subject, the method comprising administering to the subject aneffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt, stereoisomer, or tautomer thereof. 59-80. (canceled)81. The compound of claim 1, wherein the compound is of Formula (I):

or a pharmaceutically acceptable salt thereof.